U.S. patent number 6,826,033 [Application Number 10/380,627] was granted by the patent office on 2004-11-30 for aminoalcohol derivatives.
This patent grant is currently assigned to Fujisawa Pharmaceutical Co., Ltd.. Invention is credited to Naoaki Fujii, Hitoshi Hamashima, Masashi Imanishi, Hiroshi Kayakiri, Satoru Kuroda, Masayoshi Murata, Yutaka Nakajima, Hiroaki Ohtake, Minoru Sakurai, Kiyoshi Taniguchi, Yasuyo Tomishima, Kenichi Washizuka.
United States Patent |
6,826,033 |
Sakurai , et al. |
November 30, 2004 |
Aminoalcohol derivatives
Abstract
The present invention relates to a compound formula (I) wherein
X.sub.1 is bond or --O--CH.sub.2 --, (II) or (III) R.sup.1 is
hydrogen or an amino protective group, a is phenyl, indolyl or
carbazolyl, each of which may be substituted with one or two
substituent(s), and B is hydrogen; halogen; lower alkyl; lower
alkoxycarbonyl; cyclo(lower)alkyl; or a heterocyclic group,
naphthyl, 1,2,3,4-tetrahydronaphthyl, benzyl or phenyl, each of
which may be substituted with one or two substituent(s), or a salt
thereof. The compound (I) of the present invention and
pharmaceutically acceptable salts thereof are useful for the
prophylactic and/or the therapeutic treatment of pollakiures or
urinary incontinence. ##STR1##
Inventors: |
Sakurai; Minoru (Osaka,
JP), Washizuka; Kenichi (Osaka, JP),
Hamashima; Hitoshi (Osaka, JP), Tomishima; Yasuyo
(Osaka, JP), Imanishi; Masashi (Osaka, JP),
Nakajima; Yutaka (Osaka, JP), Ohtake; Hiroaki
(Osaka, JP), Kuroda; Satoru (Osaka, JP),
Murata; Masayoshi (Osaka, JP), Kayakiri; Hiroshi
(Osaka, JP), Fujii; Naoaki (South San Francisco,
CA), Taniguchi; Kiyoshi (Osaka, JP) |
Assignee: |
Fujisawa Pharmaceutical Co.,
Ltd. (Osaka, JP)
|
Family
ID: |
3824406 |
Appl.
No.: |
10/380,627 |
Filed: |
March 21, 2003 |
PCT
Filed: |
September 19, 2001 |
PCT No.: |
PCT/JP01/08155 |
371(c)(1),(2),(4) Date: |
March 21, 2003 |
PCT
Pub. No.: |
WO02/24635 |
PCT
Pub. Date: |
March 28, 2002 |
Foreign Application Priority Data
Current U.S.
Class: |
361/505; 361/506;
514/510; 514/534; 514/522; 514/332; 361/507 |
Current CPC
Class: |
C07D
231/56 (20130101); C07D 235/08 (20130101); C07D
277/56 (20130101); C07D 333/38 (20130101); C07D
217/26 (20130101); C07D 307/82 (20130101); C07D
241/20 (20130101); A61P 3/10 (20180101); C07C
275/42 (20130101); C07D 261/14 (20130101); C07D
209/18 (20130101); C07D 231/14 (20130101); C07D
209/88 (20130101); A61P 3/04 (20180101); C07C
311/08 (20130101); C07D 215/48 (20130101); C07D
213/56 (20130101); C07D 215/40 (20130101); C07D
333/70 (20130101); A61P 13/00 (20180101); C07D
241/42 (20130101); C07D 213/40 (20130101); C07D
207/416 (20130101); C07D 213/75 (20130101); C07D
249/08 (20130101); C07D 307/54 (20130101); C07D
209/40 (20130101); C07D 261/20 (20130101); C07C
233/43 (20130101); A61P 9/00 (20180101); C07D
237/28 (20130101); C07D 277/28 (20130101); A61P
3/00 (20180101); C07D 263/34 (20130101); A61P
1/00 (20180101); C07C 233/62 (20130101); C07D
217/22 (20130101); C07D 207/34 (20130101); C07D
487/04 (20130101); C07D 215/38 (20130101); C07D
307/68 (20130101); C07C 235/56 (20130101); C07D
209/08 (20130101); C07D 213/82 (20130101); C07C
275/54 (20130101); C07D 295/215 (20130101); C07C
275/40 (20130101); C07D 209/42 (20130101); C07D
307/66 (20130101); C07D 235/16 (20130101); C07D
261/18 (20130101); C07D 333/36 (20130101); C07D
333/66 (20130101); C07C 233/80 (20130101); C07D
233/90 (20130101); C07D 241/44 (20130101); C07D
215/50 (20130101); C07D 213/81 (20130101); A61P
13/02 (20180101); C07D 235/06 (20130101); C07C
2601/14 (20170501); C07C 2601/10 (20170501); C07C
2602/10 (20170501); Y02P 20/55 (20151101) |
Current International
Class: |
C07D
215/48 (20060101); C07D 333/00 (20060101); C07D
333/38 (20060101); C07C 235/56 (20060101); C07C
233/00 (20060101); C07C 311/08 (20060101); C07C
233/43 (20060101); C07D 217/00 (20060101); C07D
277/28 (20060101); C07D 333/66 (20060101); C07D
333/70 (20060101); C07D 231/56 (20060101); C07C
233/80 (20060101); C07C 311/00 (20060101); C07C
235/00 (20060101); C07D 209/40 (20060101); C07D
207/00 (20060101); C07D 487/04 (20060101); C07D
233/90 (20060101); C07D 207/34 (20060101); C07C
275/00 (20060101); C07C 275/40 (20060101); C07C
275/54 (20060101); C07D 207/416 (20060101); C07D
295/00 (20060101); C07C 275/42 (20060101); C07D
215/40 (20060101); C07D 263/34 (20060101); C07D
241/20 (20060101); C07D 307/82 (20060101); C07D
241/42 (20060101); C07D 307/66 (20060101); C07D
213/00 (20060101); C07D 307/00 (20060101); C07D
241/44 (20060101); C07D 307/54 (20060101); C07D
249/08 (20060101); C07D 241/00 (20060101); C07D
215/38 (20060101); C07D 237/00 (20060101); C07D
237/28 (20060101); C07D 209/00 (20060101); C07D
235/16 (20060101); C07D 233/00 (20060101); C07D
235/06 (20060101); C07D 235/08 (20060101); C07D
213/40 (20060101); C07D 487/00 (20060101); C07D
295/215 (20060101); C07D 235/00 (20060101); C07D
307/68 (20060101); C07D 209/42 (20060101); C07D
209/88 (20060101); C07D 209/18 (20060101); C07D
209/08 (20060101); C07D 261/20 (20060101); C07D
217/26 (20060101); C07D 215/50 (20060101); C07D
261/14 (20060101); C07D 277/00 (20060101); C07D
231/00 (20060101); C07D 263/00 (20060101); C07D
231/14 (20060101); C07D 261/00 (20060101); C07D
213/56 (20060101); C07D 213/75 (20060101); C07D
333/36 (20060101); C07D 277/56 (20060101); C07D
217/22 (20060101); C07D 213/82 (20060101); C07D
215/00 (20060101); C07D 261/18 (20060101); C07D
213/81 (20060101); C07D 249/00 (20060101); H01G
009/02 () |
Field of
Search: |
;361/505,506,507
;514/534,332,510,522,355,423,183 ;546/261,276,277 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
00 12462 |
|
Mar 2000 |
|
WO |
|
00 40560 |
|
Jul 2000 |
|
WO |
|
Other References
US. patent application Ser. No. 10/118,929, Taniguchi et al., filed
Apr. 10, 2002. .
U.S. patent application Ser. No. 10/181,970, Taniguchi et al.,
filed Aug. 6, 2002. .
U.S. patent application Ser. No. 10/380,627, Sakurai et al., filed
Mar. 21, 2003. .
U.S. patent application Ser. No. 10/380,627, Sakurai et al., filed
Mar. 21, 2003. .
U.S. patent application Ser. No. 10/746,267, Taniguchi et al.,
filed Dec. 29, 2003..
|
Primary Examiner: Nguyen; Chau N.
Assistant Examiner: Ha; Nguyen T.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier
& Neustadt, P.C.
Claims
What is claimed is:
1. A compound of the general formula [I]: ##STR196##
wherein X.sub.1 is bond or --O--CH.sub.2 --, ##STR197##
(in which R.sup.3 is hydrogen or lower alkyl), ##STR198##
(in which R.sup.4 is hydrogen or lower alkyl), ##STR199##
(in which Y.sub.2 is lower alkylene)], R.sup.1 is hydrogen or an
amino protective group, A is phenyl, indolyl or carbazolyl, each of
which may be substituted with one or two substituent(s) selected
from the group consisting of halogen, hydroxy, hydroxy(lower)alkyl
and benzyloxy, and B is hydrogen; halogen; lower alkyl; lower
alkoxycarbonyl; cyclo(lower)alkyl; or a heterocyclic group,
naphthyl, 1,2,3,4-tetrahydronaphthyl, benzyl or phenyl, each of
which may be substituted with one or two substituent(s) selected
from the group consisting of halogen, lower alkoxy, mono(or di or
tri)halo(lower)alkoxy, carboxy(lower)alkoxy, lower
alkoxycarbonyl(lower)alkoxy, phenoxy, lower alkyl, mono(or di or
tri)halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl, benzoyl, mono(or di)(lower)alkylcarbamoyl, (lower
alkylsulfonyl)carbamoyl, (lower alkylsulfonyl)-amino, (lower
alkoxycarbonyl)amino, amino, nitro, pyridyl, triazolyl, thiazolyl
optionally substituted with phenyl or lower alkyl, and phenyl
optionally substituted with mono(or di or tri)halo(lower)alkyl,
or a salt thereof.
2. A compound of claim 1, wherein X.sub.1 is bond or --O--CH.sub.2
--, ##STR200##
[in which ##STR201##
(in which R.sup.3 is hydrogen or lower alkyl), ##STR202##
(in which R.sup.4 is hydrogen or lower alkyl), ##STR203##
(in which Y.sub.2 is lower alkylene)], R.sup.1 is hydrogen, A is
phenyl which may be substituted with one or two substituent(s)
selected from the group consisting of halogen, hydroxy,
hydroxy(lower)alkyl and benzyloxy, B is pyrrolyl, imidazolyl,
pyrazolyl, pyridyl, pyrazinyl, piperidyl, indolyl, benzimidazolyl,
quinolyl, isoquinolyl, quinoxalinyl, cinnolinyl, indazolyl,
oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuranyl,
benzothienyl, naphthyl, benzyl or phenyl, each of which may be
substituted with one or two substituent(s) selected from the group
consisting of halogen, lower alkoxy, mono(or di or
tri)halo(lower)alkoxy, carboxy(lower)alkoxy, lower
alkoxycarbonyl-(lower)alkoxy, phenoxy, lower alkyl, mono(or di or
tri)halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl, benzoyl, mono(or di)(lower)alkylcarbamoyl, (lower
alkylsulfonyl)-carbamoyl, (lower alkylsulfonyl)amino, (lower
alkoxycarbonyl)amino, amino, nitro, pyridyl, triazolyl, thiazolyl
optionally substituted with phenyl or lower alkyl, and phenyl
optionally substituted with mono(or di or tri)halo(lower)alkyl.
3. A compound of claim 2, wherein X.sub.1 is --O--CH.sub.2 --,
##STR204## R.sup.1 is hydrogen, A is phenyl which may be
substituted with one or two substituent(s) selected from the group
consisting of halogen, hydroxy, hydroxy(lower)alkyl and benzyloxy,
B is pyrrolyl, pyridyl, naphthyl or phenyl, each of which may be
substituted with one or two substituent(s) selected from the group
consisting of halogen, lower alkoxy, carboxy(lower)alkoxy, lower
alkoxycarbonyl(lower)alkoxy, lower alkyl, mono(or di or
tri)halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl, mono(or di)(lower)alkylcarbamoyl, (lower
alkylsulfonyl)carbamoyl, (lower alkylsulfonyl) amino, (lower
alkoxycarbonyl) amino and nitro.
4. A compound of claim 3, which is (1)
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-1H-pyrrole-2-carboxamide; (2)
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-phenylurea; (3)
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-1-naphthamide; (4)
N-(3-fluorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l]amino]propyl]phenyl]urea; (5)
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(3-methoxyphenyl)urea,
or a salt thereof.
5. A process for preparing a compound of claim 1, or a salt
thereof, which comprises, (i) reacting a compound [II] of the
formula: ##STR205## wherein X.sub.1 and A are each as defined in
claim 1, or a salt thereof, with a compound [III] of the formula:
##STR206## wherein X.sub.2, R.sup.1 and B are each as defined in
claim 1, or a salt thereof, to give a compound [I] of the formula:
##STR207## wherein X.sub.1, X.sub.2, R.sup.1, A and B are each as
defined in claim 1, or a salt thereof, or (ii) subjecting a
compound [Ia] of the formula: ##STR208## wherein X.sub.1, X.sub.2,
A and B are each as defined in claim 1, and R.sub.a.sup.1 is an
amino protective group, or a salt thereof, to elimination reaction
of the amino protective group, to give a compound [Ib] of the
formula: ##STR209## wherein X.sub.1, X.sub.2, A and B are each as
defined in claim 1, or a salt thereof, or (iii) reacting a compound
[IV] of the formula: ##STR210## wherein X.sub.1, R.sup.1 and A are
each as defined in claim 1, or a salt thereof, with a compound [V]
of the formula: ##STR211## wherein B is as defined in claim 1, and
W.sub.1 is a leaving group, or a salt thereof, to give a compound
[Ic] of the formula: ##STR212## wherein X.sub.1, R.sup.1, A and B
are each as defined in claim 1, or a salt thereof, or (iv) reacting
a compound [Id] of the formula: ##STR213## wherein X.sub.1,
R.sup.1, A and B are each as defined in claim 1, and m is an
integer of 1 or 2, or a salt thereof, with a compound [VI] of the
formula:
6. A pharmaceutical composition which comprises, as an active
ingredient, a compound of claim 1 or a pharmaceutically acceptable
salt thereof in admixture with pharmaceutically acceptable carriers
or excipients.
7. Use of a compound of claim 1 or a pharmaceutically acceptable
salt thereof for the manufacture of a medicament.
8. A compound of claim 1 or a pharmaceutically acceptable salt
thereof for use as a medicament.
9. A method for the prophylactic and/or therapeutic treatment of
pollakiuria, urinary incontinence, obesity or diabetes, which
comprises administering a compound of claim 1 or a pharmaceutically
acceptable salt thereof to a human being or an animal.
Description
TECHNICAL FIELD
This invention relates to new aminoalcohol derivatives and salts
thereof which are beta-3 (.beta..sub.3) adrenergic receptor
agonists and useful as a medicament.
DISCLOSURE OF INVENTION
This invention relates to new aminoalcohol derivatives which are
.beta..sub.3 adrenergic receptor agonists and salts thereof.
More particularly, it relates to new aminoalcohol derivatives and
salts thereof which have gut sympathomimetic, anti-ulcerous,
anti-pancreatitis, lipolytic, anti-urinary incontinence,
anti-pollakiuria activities, anti-diabetes and anti-obesity, to
processes for the preparation thereof, to a pharmaceutical
composition comprising the same and to a method of using the same
therapeutically in the treatment and/or prevention of
gastro-intestinal disorders caused by smooth muscle contractions in
human beings or animal.
One object of this invention is to provide new and useful
aminoalcohol derivatives and salts thereof which have gut
sympathomimetic, anti-ulcerous, lipolytic, anti-urinary
incontinence, anti-pollakiuria activities, anti-diabetes and
anti-obesity.
Another object of this invention is to provide processes for the
preparation of said aminoalcohol derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical
composition comprising, as an active ingredient, said aminoalcohol
derivatives and salts thereof.
Still further object of this invention is to provide a
therapeutical method for the treatment and/or prevention of
aforesaid diseases in human beings or animals, using said
aminoalcohol derivatives and salts thereof.
The object aminoalcohol derivatives of this invention are new and
can be represented by the following formula [I]: ##STR2##
wherein X.sub.1 is bond or --O--CH.sub.2 --, ##STR3##
(in which R.sup.2 is hydrogen or lower alkyl and n is an integer of
1 or 2)
[in which ##STR4##
(in which R.sup.3 is hydrogen or lower alkyl), ##STR5##
(in which R.sup.4 is hydrogen or lower alkyl),
(in which Y.sub.2 is lower alkylene)], R.sup.1 is hydrogen or an
amino protective group, A is phenyl, indolyl or carbazolyl, each of
which may be substituted with one or two substituent(s) selected
from the group consisting of halogen, hydroxy, hydroxy(lower)alkyl
and benzyloxy, and B is hydrogen; halogen; lower alkyl; lower
alkoxycarbonyl; cyclo(lower)alkyl; or a heterocyclic group,
naphthyl, 1,2,3,4-tetrahydronaphthyl, benzyl or phenyl, each of
which may be substituted with one or two substituent(s) selected
from the group consisting of halogen, lower alkoxy, mono(or di or
tri)halo(lower)alkoxy, carboxy(lower)alkoxy, lower
alkoxycarbonyl(lower)alkoxy, phenoxy, lower alkyl, mono(or di or
tri)-halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl, benzoyl, mono(or di)(lower)-alkylcarbamoyl, (lower
alkylsulfonyl)carbamoyl, (lower alkylsulfonyl)amino, (lower
alkoxycarbonyl)amino, amino, nitro, pyridyl, triazolyl, thiazolyl
optionally substituted with phenyl or lower alkyl, and phenyl
optionally substituted with mono(or di or tri)halo(lower)alkyl,
or a salt thereof.
The object compound [I] or a salt thereof can be prepared by the
following processes. ##STR6## ##STR7## wherein X.sub.1, X.sub.2,
R.sup.1, A and B are each as defined above, R.sub.a.sup.1 is an
amino protective group, R.sub.a.sup.2 is lower alkyl, W.sub.1 is a
leaving group, W.sub.2 is an acid residue, m is an integer of 1 or
2, k is 0 or an integer of 1, and P is polymer.
In the above and subsequent description of the present
specification, suitable examples of the various definition to be
included within the scope of the invention are explained in detail
in the following.
The term "lower" is intended to mean a group having 1 to 6,
preferably 1 to 4, carbon atom(s), unless otherewise provided.
Suitable example of "lower alkyl" and "lower alkyl" moiety in the
terms of "hydroxy(lower)alkyl", "mono(or di or
tri)halo(lower)alkyl", etc. may include straight or branched one
having 1 to 6 carbon atom(s), such as methyl, ethyl propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, and the
like.
Suitable "lower alkoxy" and "lower alkoxy" moiety in the terms of
"lower alkoxycarbonyl", "carboxy(lower)alkoxy", etc. may be a
straight or branched one such as methoxy, ethoxy, propoxy,
isopropoxy, 1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy,
pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and the like, in
which the preferred one may be C.sub.1 -C.sub.4 alkoxy, and the
most preferred one may be methoxy or ethoxy.
Suitable "lower alkylene" may include straight or branched one such
as methylene, ethylene, trimethylene, tetramethylene,
pentamethylene, hexamethylene, methylmethylene, ethylethylene,
propylene, and the like, in which more preferable example may be
C.sub.1 -C.sub.4 alkylene and the most preferable one may be
trimethylene.
Suitable example of "halogen" may be fluoro, chloro, bromo and
iodo.
Suitable "cyclo(lower)alkyl" may include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl, in which the preferred one may be
cyclohexyl.
Suitable "lower alkanoyl" may be formyl, acetyl, propanoyl,
butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl,
hexanoyl and the like, in which the preferred one may be
acetyl.
Suitable "mono(or di or tri)halo(lower)alkyl" may be fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or
2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl,
1,1-difluoroethyl, 2,2-difluoroethyl, and the like, in which the
preferred one may be trifluoromethyl.
Suitable example of "heterocyclic group" may include unsaturated 3
to 8-membered (more preferably 5 or 6-membered) heteromonocyclic
group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl,
pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),
tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 to 4 nitrogen atom(s), for
example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,
etc.; unsaturated condensed heterocyclic group containing 1 to 4
nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indazolyl,
benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably
5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen
atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl,
isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; saturated 3 to
8-membered (more preferably 5 or 6-membered) heteromonocyclic group
containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for
example, morpholinyl, sydnonyl, etc.; unsaturated condensed
heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3
nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3
nitrogen atom(s), for example, thiazolyl, isothiazolyl,
thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl,
etc.; saturated 3 to 8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3
nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3
to 8-membered (more preferably 5 or 6-membered) heteromonocyclic
group containing 1 or 2 sulfur atom(s), for example, thienyl,
dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed
heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3
nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl,
imidazothiadiazolyl, etc.; unsaturated 3 to 8-membered (more
preferably 5 or 6-membered) heteromonocyclic group containing an
oxygen atom, for example, furyl, etc.; saturated 3 to 8-membered
(more preferably 5 or 6-membered) heteromonocyclic group containing
an oxygen atom, for example, tetrahydrofuran, tetrahydropyran,
etc.; unsaturated condensed heterocyclic group containing 1 or 2
oxygen atom(s), for example, benzofuranyl, etc.; unsaturated 3 to
8-membered (more preferably 5 or 6-membered) heteromonocyclic group
containing an oxygen atom and 1 or 2 sulfur atom(s), for example,
dihydrooxathiinyl, etc.; unsaturated condensed heterocyclic group
containing 1 or 2 sulfur atom(s), for example, benzothienyl,
benzodithiinyl, etc.; unsaturated condensed heterocyclic group
containing an oxygen atom and 1 or 2 sulfur atom(s), for example,
benzoxathiinyl, etc.; 2-oxo-2,3-dihydro-1H-benzimidazolyl; and the
like.
Suitable example of "polymer" may be polystyrene which may be used
for a solid phase support linkage method mentioned below.
Suitable "leaving group" may include hydroxy, reactive group
derived from hydroxy and the like.
Suitable "reactive group derived from hydroxy" may include an acid
residue and the like.
Suitable "acid residue" may include halogen (e.g. fluoro, chloro,
bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and
the like.
Suitable example of "amino protective group" moiety may be common
amino protective group such as acyl, for example, substituted or
unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl,
trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g.
tert-butoxycarbonyl, tert-amyloxy-carbonyl, etc.], substituted or
unsubstituted aralkyloxy-carbonyl [e.g. benzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted
arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.],
nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl, etc.],
and the like, in which preferable one is phenyl(lower)alkyl such as
benzyl.
Suitable salts of the object aminoalcohol derivative [I] are
pharmaceutically acceptable salts and include conventional
non-toxic salts such as an inorganic acid addition salt [e.g.
hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic
acid addition salt [e.g. formate, acetate, trifluoroacetate,
oxalate, maleate, fumarate, tartarate, citrate, methanesulfonate,
benzenesulfonate, toluenesulfonate, etc.] or the like.
The Processes 1 to 5 for preparing the object compound [I] of the
present invention are explained in detail in the following.
Process 1
The object compound [I] or a salt thereof can be prepared by
reacting a compound [II] or a salt thereof with a compound [III] or
a salt thereof.
Suitable salt of the compounds [II] and [III] may be the same as
those exemplified for the compound [I].
The reaction is preferably carried out in the presence of a base
such as an alkali metal carbonate [e.g. sodium carbonate, potassium
carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium
carbonate, calcium carbonate, etc.], an alkali metal bicarbonate
[e.g. sodium bicarbonate, potassium bicarbonate, etc.],
tri(lower)alkylamine [e.g. trimethylamine, triethylamine, etc.],
picoline or the like.
The reaction is usually carried out in a conventional solvent, such
as an alcohol [e.g. methanol, ethanol, propanol, isopropanol,
etc.], diethyl ether, tetrahydrofuran, dioxane, or any other
organic solvent which does not adversely influence the
reaction.
The reaction temperature is not critical, and the reaction can be
carried out under cooling to heating.
Process 2
The object compound [Ib] or a salt thereof can be prepared by
subjecting a compound [Ia] or a salt thereof to elimination
reaction of the amino protective group.
Suitable salts of the compounds [Ia] and [Ib] may be the same as
those exemplified for the compound [I].
This reaction can be carried out in the manner disclosed in
Examples 2 or 11.
Process 3
The object compound [Ic] or a salt thereof can be prepared by
reacting the compound [IV] or a salt thereof with the compound [V]
or a salt thereof.
Suitable salt of the compounds [Ic], [V] and [IV] may be the same
as those exemplified for the compound [I].
This reaction is usually carried out in a solvent such as alcohol
[e.g. methanol, ethanol, etc.], dichloromethane, benzene,
N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other
solvent which does not adversely affect the reaction.
The reaction may be carried out in the presence of an inorganic or
an organic base such as an alkali metal hydroxide [e.g. sodium
hydroxide, potassium hydroxide, etc.], an alkali metal carbonate
[e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal
bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.],
alkali metal hydride [e.g. sodium hydride, potassium hydride,
etc.], tri(lower)alkylamine [e.g. trimethylamine, triethylamine,
diisopropylethylamine, etc.], pyridine or its derivative [e.g.
picoline, lutidine, 4-dimethylaminopyridine, etc.], or the like. In
case that the base to be used in liquid, it can also be used as a
solvent.
This reaction can be also carried out in the manner disclosed in
Example 60, 61 or 62 or similar manners thereto.
The reaction temperature is not critical, and the reaction can be
carried out under cooling, at room temperature or under warming or
heating.
Process 4
The object compound [Ie] or a salt thereof can be prepared by
reacting the compound [Id] or a salt thereof with the compound
[VI].
Suitable salt of the compound [Id] and [Ie] may be the same as
those exemplified for the compound [I].
This reaction is usually carried out in a conventional solvent such
as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,
acetonitrile, chloroform, dichloromethane, ethylene chloride,
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
N,N-dimethylacetamide, pyridine or any other organic solvent which
does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is
usually carried out under cooling to warming.
The reaction may also be carried out in the presence of an
inorganic or organic base such as an alkali metal bicarbonate,
tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine,
N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the
like.
Process 5
The object compound [If] or a salt thereof can be prepared by
subjecting the compound [IV] or a salt thereof with the compound
[VII] or a salt thereof.
Suitable salts of the compounds [If], [IV] and [VII] may be the
same as those exemplified for the compound [I].
This reaction can be carried out in the manner disclosed in Example
1 or 3 or similar manners thereto.
This reaction can be also carried out in the manner disclosed in
Example 64 or 66 or similar manners thereto.
Process 6
The object compound [Ic] or a salt thereof can be prepared by means
of a solid phase support linkage method, namely by reacting a
compound [VIII] with compound [IX] or a salt thereof and then by
reacting the resultant compound [.alpha.]with a compound [IV] or a
salt thereof.
Suitable salt of the compounds [Ic], [IV], [VIII], [IX] and
[.alpha.]may be the same as those exemplified for the compound
[I].
This reaction can be carried out in the manner disclosed in Example
59 or similar manner thereto.
The compounds obtained by the above processes can be isolated and
purified by a conventional method such as pulverization,
recrystallization, column chromatography, reprecipitation, or the
like, and converted to the desired salt in conventional manners, if
necessary.
It is to be noted that the compound [I] and the other compounds may
include one or more stereoisomers due to asymmetric carbon atoms,
and all of such isomers and mixture thereof are included within the
scope of this invention.
It is further to be noted that isomerization or rearrangement of
the object compound [I] may occur due to the effect of the light,
acid, base or the like, and the compound obtained as the result of
said isomerization or rearrangement is also included within the
scope of the present invention.
It is also to be noted that the solvating form of the compound [I]
(e.g. hydrate, etc.) and any form of the crystal of the compound
[I] are included within the scope of the present invention.
The object compound [I] or a salt thereof possesses gut
sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic,
anti-urinary incontinence and anti-pollakiuria activities, and are
useful for the treatment and/or prevention of gastro-intestinal
disorders caused by smooth muscle contractions in human beings or
animals, and more particularly for the treatment and/or prevention
of spasm or hyperanakinesia in case of irritable bowel syndrome,
gastritis, gastric ulcer, duodenal ulcer, enteritis,
cholecystopathy, cholangitis, urinary calculus and the like; for
the treatment and/or prevention of ulcer such as gastric ulcer,
duodenal ulcer, peptic ulcer, ulcer caused by non steroidal
anti-inflammatory drugs, or the like; for the treatment and/or
prevention of dysuria such as pollakiuria, urinary incontinence or
the like in case of nervous pollakiuria, neurogenic bladder
dysfunction, nocturia, unstable bladder, cystospasm, chronic
cystitis, chronic prostatitis, prostatic hypertrophy or the like;
for the treatment and/or prevention of pancreatitis, obesity,
diabetes, glycosuria, hyperlipidemia, hypertension,
atherosclerosis, glaucoma, melancholia, depression or the like; for
the treatment and/or prevention of diseases as the result of
insulin resistance (e.g. hypertension, hyperinsulinemia, etc.); for
the treatment and/or prevention of neurogenetic inflammation; and
for reducing a wasting condition, and the like.
Additionally, .beta..sub.3 adrenergic receptor agonists are known
to lower triglyceride and cholesterol levels and to raise high
density lipoprotein levels in mammals (U.S. Pat. No. 5,451,677).
Accordingly, the object compound [I] is useful in the treatment
and/or prevention of conditions such as hyper-triglyceridaemia,
hypercholesterolaemia and in lowering high density lipoprotein
levels as well as in the treatment of atherosclerotic and
cardiovascular diseases and related conditions.
Moreover, the object compound [I] is useful for inhibiting uterine
contractions, preventing premature labor, and treating and
preventing dysmenorrhea.
In order to show the usefulness of the compound [I] for the
prophylactic and therapeutic treatment of above-mentioned disease
in human beings or animals, the pharmacological test data of a
representative compound thereof are shown in the following.
Test
Effect on the increase in intravesical pressure induced by
carbachol in anesthetized dog
Test Compound (1)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]pheny
l]-1H-pyrrole-2-carboxamide
Test Method
Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours
and maintained under halothane anesthesia. A 12F Foley catheter was
lubricated with water soluble jelly, inserted into the urethral
orifice and advanced approximately 10 cm until the balloon tip was
placed well inside the bladder. The balloon was then inflated with
5 ml of room air and catheter slowly withdrawn just part the first
resistance that is felt at the bladder neck. Urine was completely
drained out through the catheter, and 30 ml of biological saline
was infused. The catheter was connected to pressure transducer, and
intravesical pressure was continuously recorded. The test compound
was injected by intra-duodena route at 30 minutes before the
administration of carbachol (1.8 .mu.g/kg).
Test Results Treatment Increase in intravesical pressure (mmHg)
Control 7.0 .+-. 1.0 Test Compound (1) 2.6 .+-. 0.05 (0.32 mg/kg)
(N = 2)
Preferred embodiments of the object compound [I] are as follow:
X.sub.1 is bond or --O--CH.sub.2 --, ##STR8##
(in which R.sup.2 is hydrogen or lower alkyl (more preferably
C.sub.1 -C.sub.4 alkyl, most preferably methyl) and n is an integer
of 1 or 2) ##STR9##
(in which Y.sub.1 is ##STR10##
(in which R.sup.3 is hydrogen or lower alkyl (more preferably
C.sub.1 -C.sub.4 alkyl, most preferably methyl)), ##STR11##
(in which R.sup.4 is hydrogen or lower alkyl (more preferably
C.sub.1 -C.sub.4 alkyl, most preferably methyl)), --CH.sub.2
CH.sub.2 --, --CH.dbd.CH-- or ##STR12##
(in which Y.sub.2 is lower alkylene (more preferably C.sub.2
-C.sub.4 alkylene, most preferably trimethylene))], R.sup.1 is
hydrogen, A is phenyl which may be substituted with one or two
substituent(s) selected from the group consisting of halogen,
hydroxy, hydroxy(lower)alkyl (more preferably hydroxy(C.sub.1
-C.sub.4)alkyl, most preferably hydroxymethyl) or benzyloxy, B is
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, piperidyl,
indolyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,
cinnolinyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl,
furyl, benzofuranyl, benzothienyl, naphthyl, benzyl or phenyl, each
of which may be substituted with one or two substituent(s) selected
from the group consisting of halogen (more preferably fluoro or
chloro), lower alkoxy (more preferably C.sub.1 -C.sub.4 alkoxy,
most preferably methoxy), mono(or di or tri)halo(lower)alkoxy (more
preferably mono(or di or tri)(C.sub.1 -C.sub.4)alkoxy, most
preferably trifluoromethoxy), carboxy(lower)alkoxy (more preferably
carboxy(C.sub.1 -C.sub.4)alkoxy, most preferably carboxymethoxy),
lower alkoxycarbonyl(lower)alkoxy (more preferably C.sub.1 -C.sub.4
alkoxycarbonyl(C.sub.1 -C.sub.4)alkoxy, most preferably
ethoxycarbonylmethoxy), phenoxy, lower alkyl (more preferably
C.sub.1 -C.sub.4 alkyl, most preferably methyl), mono(or di or
tri)halo(lower)alkyl (more preferably mono(or di or
tri)halo(C.sub.1 -C.sub.4)alkyl, most preferably trifluoromethyl),
cyano, carboxy, lower alkoxycarbonyl (more preferably C.sub.1
-C.sub.4 alkoxycarbonyl, most preferably ethoxycarbonyl), lower
alkanoyl (more preferably C.sub.1 -C.sub.4 alkanoyl, most
preferably acetyl), benzoyl, mono(or di)(lower)alkylcarbamoyl (more
preferably mono(or di)(C.sub.1 -C.sub.4)alkylcarbamoyl, most
preferably dimethylcarbamoyl), (lower alkylsulfonyl)carbamoyl(more
preferably (C.sub.1 -C.sub.4 alkylsulfonyl)carbamoyl, most
preferably (methanesulfonyl)carbamoyl), (lower alkylsulfonyl)amino
(more preferably (C.sub.1 -C.sub.4 alkylsulfonyl)amino, most
preferably (methanesulfonyl)amino), (lower alkoxycarbonyl)amino
(more preferably (C.sub.1 -C.sub.4 alkoxycarbonyl)amino, most
preferably (methoxycarbonyl)amino), amino, nitro, pyridyl,
triazolyl, thiazolyl optionally substituted with phenyl or lower
alkyl (more preferably C.sub.1 -C.sub.4 alkyl, most preferably
methyl), and phenyl optionally substituted with mono(or di or
tri)halo(lower)alkyl (more preferably mono(or di or
tri)halo(C.sub.1 -C.sub.4)alkyl, most preferably
trifluoromethyl).
More preferred embodiments of the object compound [I] are as
follow: X.sub.1 is --O--CH.sub.2 ##STR13##
(in which R.sup.2 is hydrogen and n is an integer of 1) or
##STR14## R.sup.1 is hydrogen, A is phenyl which may be substituted
with one or two substituent(s) selected from the group consisting
of halogen, hydroxy, hydroxy(lower)alkyl and benzyloxy, B is
pyrrolyl, pyridyl, naphthyl or phenyl, each of which may be
substituted with one or two substituent(s) selected from the group
consisting of halogen, lower alkoxy, carboxy(lower)alkoxy, lower
alkoxycarbonyl-(lower)alkoxy, lower alkyl, mono(or di or
tri)halo-(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl, mono(or di) (lower)alkylcarbamoyl, (lower
alkylsulfonyl)carbamoyl, (lower alkylsulfonyl)-amino, (lower
alkoxycarbonyl)amino and nitro.
The following Preparations and Examples are given for the purpose
of illustrating this invention.
Preparation 1
A mixture of (2S)-2-(phenoxymethyl)oxirane (2.30 g),
(2S)-2-amino-3-(4-nitrophenyl)-1-propanol (3.0 g) and ethanol (30
ml) was heated under reflux for 18 hours. The reaction mixture was
evaporated in vacuo. The residue was triturated with ethyl acetate
to give
(2S)-3-(4-nitrophenyl)-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-1-propano
l (3.97 g) as a pale yellow powder. This powder was used for the
next step without further purification.
Preparation 2
A mixture of
(2S)-3-(4-nitrophenyl)-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-1-propano
l (3.97 g), di-tert-butyl dicarbonate (3.0 g) and tetrahydrofuran
(40 ml) was stirred at room temperature for 20 hours. The reaction
mixture was evaporated in vacuo. The residue was triturated with
ether to give tert-butyl
N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)-ethyl]-N-((2S)-2-hydroxy-3-phenoxyprop
yl)carbamate (4.39 g) as a white powder.
NMR (CDCl.sub.3, .delta.): 1.62 (9H, s), 2.15-4.20 (10H, m),
6.78-7.22 (7H, m), 8.18 (2H, d, J=8 Hz)
Preparation 3
A mixture of tert-butyl
N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]-N-((2S)-2-hydroxy-3-phenoxypropy
l)-carbamate (4.29 g), 10% palladium on carbon (50% wet, 429 mg),
methanol (43 ml) and tetrahydrofuran (22 ml) was stirred at room
temperature under hydrogen atmosphere (1 atm) for 4 hours. The
catalyst was removed by vacuum filtration through celite and rinsed
with methanol. The filtrate and washings were combined and
evaporated in vacuo to give a colorless oil (4.19 g). The residue
was purified by a silica gel column chromatography (silica gel 250
g, eluting with hexane:ethyl acetate=1:1) to give the first crop of
tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropy
l)carbamate (2.85 g) as a colorless syrup and the second crop (527
mg) as a colorless syrup.
NMR (CDCl.sub.3, .delta.): 1.48 (9H, s), 2.40-4.40 (10H, m), 6.62
(2H, d, J=8 Hz), 6.8-7.40 (7H, m)
Preparation 4
A mixture of (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (15.0 g),
di-tert-butyl dicarbonate (20.0 g) and tetrahydrofuran (120 ml) was
stirred at room temperature for 1.5 hours. The reaction mixture was
evaporated in vacuo. The residue was triturated with ether to give
tert-butyl N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate
(19.82 g) as a white powder.
NMR (CDCl.sub.3, .delta.): 1.40 (9H, s), 2.16 (1H, t, J=4 Hz), 2.98
(2H, d, J=6 Hz), 3.50-3.78 (2H, m), 3.90 (1H, m), 4.82 (1H, d, J=6
Hz), 7.41 (2H, d, J=8 Hz), 8.18 (2H, d, J=8 Hz)
Preparation 5
A mixture of tert-butyl
N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (22.3 g),
2,2-dimethoxypropane (46.3 ml), p-toluenesulfonic acid monohydrate
(1.43 g) and dichloromethane (200 ml) was stirred at room
temperature for 15 hours. The reaction mixture was washed with
saturated aqueous sodium bicarbonate and brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
triturated with isopropyl ether to give tert-butyl
(S)-4-(4-nitrobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(16.9 g) as a pale yellow powder.
NMR (CDCl.sub.3, .delta.): 1.42-1.68 (15H, m), 2.84 (1H, dd, J=15,
10 Hz), 3.26 (1H, br), 3.72 (1H, d, J=10 Hz), 3.86 (1H, dd, J=10, 7
Hz), 4.10 (1H, br), 7.40 (2H, br), 8.20 (2H, br)
Preparation 6
A mixture of tert-butyl
(S)-4-(4-nitrobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(22.25 g), 10% palladium on carbon (50% wet, 2.23 g) methanol (223
ml) and tetrahydrofuran (112 ml) was stirred at room temperature
under hydrogen atmosphere (4 atm) for 1.5 hours. The catalyst was
removed by vacuum filtration through celite and rinsed with
methanol. The filtrate and washings were combined and evaporated in
vacuo to give a colorless oil (20.82 g). The residue was purified
by a silica gel column chromatography (silica gel 250 g, elution
with hexane:ethyl acetate=3:1) to give tert-butyl
(S)-4-(4-aminobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate as
a pale yellow syrup (19.43 g).
NMR (CDCl.sub.3, .delta.): 1.40-1.68 (15H, m), 2.66 (1H, dd, J=12,
10 Hz), 3.06 (1H, br), 3.50-4.04 (3H, m), 7.62 (2H, br d, J=8 Hz),
7.02 (2H, br)
Preparation 7
A suspension of (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (5.89 g)
and benzaldehyde (3.39 g) in dichloromethane (59 ml) was stirred at
room temperature for 2.5 hours. The mixture was evaporated, and the
residual solid was suspended in ethanol (47 ml)-dichloromethane
(11.8 ml). Sodium borohydride (1.25 g) was slowly added to the
suspension, and the mixture was stirred at room temperature for 5
hours. The mixture was poured onto water (47 ml) and stirred at
room temperature for 15 minutes. The precipitate formed was
collected by filtration, washed with water, and dried in vacuo. The
crude product was recrystallized from ethanol to give
(2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (5.18 g) as a
pale yellow powder. The filtrates obtained above were combined,
concentrated, and partitioned between chloroform and water. The
organic layer was separated, washed successively with water and
brine, dried over magnesium sulfate, and filtered. The filtrate was
concentrated and the residue was purified by column chromatography
(silica gel, chloroform/methanol) to give the additional amount of
product (2.78 g) as a white powder.
NMR (CDCl.sub.3, .delta.): 2.72-3.12 (3H, m), 3.35 (1H, dd, J=11
and 4 Hz), 3.64 (1H, dd, J=11 and 4 Hz), 3.80 (2H, s), 7.08-7.48
(7H, m), 8.14 (2H, d, J=9 Hz)
MS m/z: 287 (M.sup.+ +1)
Preparation 8
A mixture of (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol
(1.15 g) and (2S)-2-(phenoxymethyl)oxirane (661 mg) in ethanol (9.2
ml) was heated to reflux for 3 hours. After allowed to cool to room
temperature, the mixture was concentrated and the residue was
purified by column chromatography (silica gel, hexane/ethyl
acetate) to give
(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino]-3-(4-nitrophenyl
)-1-propanol (1.17 g) as a pale yellow solid.
NMR (CDCl.sub.3, .delta.): 2.60-3.12 (4H, m), 3.12-3.32 (1H, m),
3.40-3.75 (3H, m), 3.75-4.08 (4H, m), 6.84 (2H, d, J=9 Hz),
6.90-7.02 (1H, m), 7.10-7.40 (9H, m), 8.11 (2H, d, J=9 Hz)
MS m/z: 437 (M.sup.+ +1)
Preparation 9
To a suspension of
(2S)-2-[(N-benzyl-N-((2S)-2-hydroxy-3-phenoxypropyl]amino]-3-(4-nitropheny
l)-1-propanol (1.12 g) in ethanol (11 ml)--water (2.2 ml) were
added powdered iron (573 mg) and ammonium chloride (55 mg). The
mixture was gently heated to reflux for 1 hour and allowed to cool
to room temperature. After the insoluble material was filtered off,
the filtrate was concentrated and partitioned between chloroform
and water. The organic layer was separated, washed successively
with water and brine, dried over magnesium sulfate, and filtered.
The filtrate was concentrated and the residue was purified by
column chromatography (silica gel, hexane/ethyl acetate) to give
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino
]-1-propanol (990 mg) as a pale yellow oil.
NMR (CDCl.sub.3, .delta.): 2.44 (1H, dd, J=14 and 9 Hz), 2.70-3.20
(4H, m), 3.42-4.02 (7H, m), 6.61 (2H, d, J=8 Hz), 6.82 (2H, d, J=9
Hz), 6.86-7.02 (3H, m), 7.13-7.40 (7H, m)
MS m/z: 407 (M.sup.+ +1)
Preparation 10
To a mixture of
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-benzamide (102 mg) and triethylamine (0.1 ml) in
dichloromethane (1 ml) was added acetic anhydride (50 .mu.l), and
the mixture was stirred at room temperature for 5 hours. The
mixture was partitioned between ethyl acetate and water. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated to
give
N-[4-[(2S)-3-acetoxy-2-[N-[(2S)-2-acetoxy-3-phenoxypropyl]-N-benzylamino]p
ropyl]phenyl]-benzamide (124 mg) as a white amorphous powder.
NMR (CDCl.sub.3, .delta.): 1.91 (3H, s), 2.04 (3H, s), 2.50-3.40
(5H, m), 3.68-4.24 (6H, m), 4.98-5.20 (1H, m), 6.74-7.02 (3H, m),
7.13 (2H, d, J=9 Hz), 7.16-7.35 (7H, m), 7.42-7.60 (5H, m), 7.77
(1H, br s), 7.80-7.92 (2H, m)
MS m/z: 595 (M.sup.+ +1)
Preparation 11
To an ice-cooled solution of tert-butyl
(S)-4-(4-aminobenzenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(500 mg) and pyridine (0.16 ml) in dichloromethane (60 ml) was
added dropwise benzoyl chloride (0.21 ml). The mixture was stirred
at the same temperature for 1 hour and partitioned between
chloroform and saturated sodium bicarbonate solution. The organic
layer was separated, washed with brine, dried over magnesium
sulfate, and filtered. The filtrate was concentrated and the
residue was purified by column chromatography (silica gel,
hexane/ethyl acetate) to give tert-butyl
(S)-4-[4-(benzoylamino)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(690 mg) as colorless oil.
NMR (CDCl.sub.3, .delta.): 2.80-3.00 (2H, m), 3.40-3.80 (3H, m),
7.00-7.50 (9H, m)
MS m/z: 286 (M.sup.+ +1)
Preparation 12
To a solution of tert-butyl
(S)-4-[4-(benzoylamino)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(690 mg) in methanol (20 ml) was added 4N hydrogen chloride in
ethyl acetate (5 ml) at room temperature, and the solution was
stirred at the same temperature for 4 hours. The mixture was
evaporated in vacuo, and the residue was partitioned between
chloroform and saturated sodium bicarbonate solution. The organic
layer was separated, washed with brine, dried over magnesium
sulfate, and filtered. The filtrate was concentrated to give
(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]benzamide (250 mg) as a
colorless solid.
NMR (MeOD-d.sub.4, .delta.): 2.95 (2H, d, J=7 Hz), 3.40-3.80 (3H,
m), 7.30 (2H, d, J=8 Hz), 7.40-8.00 (7H, m)
MS m/z: 271 (M.sup.+ +1)
Preparation 13
To an ice-cooled solution of tert-butyl
(S)-4-(4-aminobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(1.0 g) in dichloromethane (10 ml) was added dropwise phenyl
isocyanate (0.39 ml). The mixture was stirred at the same
temperature for 1 hour and partitioned between chloroform and
saturated sodium bicarbonate solution. The organic layer was
separated, washed with brine, dried over magnesium sulfate, and
filtered. The filtrate was concentrated and the residue was
purified by column chromatography (silica gel, hexane/ethyl
acetate) to give tert-butyl
(S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-ca
rboxylate (1.48 g) as colorless oil.
NMR (CDCl.sub.3, .delta.): 1.50-1.70 (15H, m), 2.60 (1H, dd, J=10,
13 Hz), 3.00-3.20 (1H, m), 3.70-3.80 (2H, m), 4.05-4.10 (1H, m),
6.88-7.40 (9H, m)
Preparation 14
To a solution of tert-butyl
(S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-ca
rboxylate (1.48 g) in methanol (20 ml) was added 4N hydrogen
chloride in ethyl acetate (5 ml) at room temperature, and the
solution was stirred at the same temperature for 4 hours. The
mixture was evaporated in vacuo, and the residue was triturated
with diisopropyl ether to give
(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N'-phenylurea
hydrochloride (660 mg) as a colorless solide.
NMR (MeOD-d.sub.4, .delta.): 2.80-3.00 (2H, m), 3.40-3.80 (3H, m),
7.00-7.50 (9H, m)
MS m/z: 286 (M.sup.+ +1)
Preparation 15
To a solution of (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl)benzamide
(207 mg) and benzaldehyde (106 mg) in 1,4-dioxane (5 ml) was
refluxed for 3 hours, and the mixture was evaporated in vacuo. To
the residue in methanol (5 ml) was added sodium borohydride (15 mg)
on ice-cooling, and stirred at the same temperature for 1 hour. The
resulting mixture was poured into saturated aqueous sodium
bicarbonate solution, and extracted with ethyl acetate. The organic
layer was washed with brine, dried over magnesium sulfate, and
evaporated in vacuo. The residue was chromatographed (hexane-ethyl
acetate) over silica gel to afford
(S)-N-[4-[2-(benzylamino)-3-hydroxypropyl]phenyl]benzamide (250 mg)
as colorless oil.
NMR (CDCl.sub.3, .delta.): 2.70-2.83 (2H, m), 2.88-2.98 (1H, m),
3.35 (1H, dd, J=5, 11 Hz), 3.68 (1H, dd, J=4, 11 Hz), 3.79 (2H, s),
7.10-7.90 (14H, m)
MS m/z: 361 (M.sup.+ +1)
Preparation 16
To an ice-cooled solution of
(2S)-1,2-epoxy-3-(3-formyl-4-benzyloxyphenoxy)propane (2.6 g) in
methanol (30 ml) was added sodium borohydride (381 mg). The mixture
was stirred at the same temperature for 1 hour and partitioned
between chloroform and saturated sodium bicarbonate solution. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated to
give (2S)-1,2-epoxy-3-(3-hydroxymethyl-4-benzyloxyphenoxy)propane
(2.57 g) as a yellow oil.
NMR (CDCl.sub.3, .delta.): 2.74 (1H, q, J=3 Hz), 2.89 (1H, t, J=5
Hz), 3.33 (1H, m), 3.92 (2H, dd, J=5, 11 Hz), 4.20 (1H, dd, J=3, 11
Hz), 4.70 (2H, d, J=6 Hz), 5.1 (2H, s), 6.70-7.00 (3H, m),
7.32-7.45 (5H, m)
MS m/z: 309 (M.sup.+ +Na)
Preparation 17
To a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropy
l)carbamate (200 mg) in 1,2-dichloroethane (2.0 ml) was added
N,O-bis(trimethylsilyl)acetamide (119 .mu.l) at room temperature
and the solution was stirred for 30 minutes. To the solution was
added successively ethyl 2-isocyanatobenzoate (110 mg) and
N,N-diisopropylethylamine (8.36 .mu.l) and the mixture was stirred
for 2 hours. The reaction mixture was diluted with ethyl acetate
(20 ml) and washed with water (20 ml.times.1) and brine (20
ml.times.1) successively, dried over magnesium sulfate, and
evaporated to give a pale yellow foam. The crude product was
purified by a recycling preparative high pressure liquid
chromatography equipped with a gel permeation chromatography column
(eluent: chloroform) and silica gel chromatography (eluent:
hexane/ethyl acetate=2/1) to give ethyl
2-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl
)amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate
(217 mg) as a white foam.
MS (ESI) m/z: 702 (M+Na.sup.+)
Preparation 18
The following compounds were obtained according to a similar manner
to that of Preparation 17. (1) Ethyl
3-[[[[4-[(2S)-2-[(N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropy
l)amino]-3-[(trimethylsilyl)-oxy]propyl]phenyl]amino]carbonyl]amino]benzoat
e
MS (ESI) m/z: 702 (M+Na.sup.+) (2) Ethyl
4-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl
)amino]-3-[(trimethylsilyl)-oxy]propyl]phenyl]amino]carbonyl]amino]benzoate
MS (ESI) m/z: 702 (M+Na.sup.+)
Preparation 19
To a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropy
l)carbamate (100 mg) in 1,2-dichloroethane (1.0 ml) was added
N,O-bis(trimethylsilyl)acetamide (59.3 .mu.l) at room temperature
and the solution was stirred for 30 minutes. To the solution was
added successively 2-nitrophenyl isocyanate (47.3 mg) and 1.0 M
solution of N,N-diisopropylethylamine in 1,2-dichloroethane (24
.mu.l) and the mixture was stirred for 90 minutes. To the mixture
was added an additional portion of N,O-bis(trimethylsilyl)acetamide
(59.3 .mu.l ) and the whole was stirred overnight. The reaction
mixture was diluted with ethyl acetate (20 ml) and washed with
water (20 ml.times.1) and brine (20 ml.times.1) successively, dried
over magnesium sulfate, and evaporated to give a yellow foam. The
crude product was purified by a recycling preparative high pressure
liquid chromatography equipped with a gel permeation chromatography
column (eluent: chloroform) and silica gel chromatography (eluent:
hexane/ethyl acetate=4/1) to give tert-butyl
N-[(1S)-1-[4-[[[(2-nitrophenyl)-amino]carbonyl]amino]benzyl]-2-[(trimethyl
silyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamate
(100 mg) as a yellow foam.
MS m/z: 747 (M+Na.sup.+)
Preparation 20
The following compounds were obtained according to a similar manner
to that of Preparation 19. (1) tert-Butyl
N-[(1S)-1-[4-[[[(3-nitrophenyl]amino]-carbonyl]amino]benzyl]-2-[(trimethyl
silyl)oxy]ethyl)-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamate
MS m/z: 747 (MH.sup.+) (2) tert-Butyl
N-[(1S)-1-[4-[[[(4-nitrophenyl)amino]-carbonyl]amino]benzyl]-2-[(trimethyl
silyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamate
MS m/z: 747 (MH.sup.+)
Preparation 21
To a suspension of
(25)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (6.0 g) in
ethanol (60 ml) was added (2R)-2-(3-chlorophenyl)oxirane (4.86 g)
and the mixture was refluxed for 23 hours. After cooling to room
temperature, the solvent was removed by evaporation and the residue
was chromatographed on silica gel (eluent: hexane/ethyl
acetate=2/1) to give the
(2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nit
rophenyl)-1-propanol (5.46 g) as a yellow crystalline solid.
MS m/z: 440 (MH.sup.+)
Preparation 22
To a solution of
(2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nit
rophenyl)-1-propanol (5.33 g) in a mixed solvent of methanol (50
ml) and chlorobenzene (50 ml) was added 10% palladium on activated
carbon (50% wet, 1.00 g) and the mixture was hydrogenated at 1 atm
for 2 hours. The catalyst was filtered off and washed with
methanol. The filtrate was concentrated in vacuo to give
(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1
-propanol dihydrochloride (4.95 g) as a pale yellow solid.
MS m/z: 321 (MH.sup.+)
Preparation 23
To a suspension of
(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1
-propanol dihydrochloride (3.68 g) in a mixed solvent of chloroform
and methanol (9:1, 75 ml) was added a saturated aqueous sodium
bicarbonate solution (75 ml) and the whole was stirred vigorously.
The organic layer was separated and the aqueous layer was extracted
with a mixed solvent of chloroform and methanol (9:1, 25
ml.times.5). The organic layers were combined, dried over magnesium
sulfate, filtered, and evaporated to give
(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1
-propanol (2.78 g) as a pale orange crystalline solid.
Preparation 24
To a solution of
(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1
-propanol (2.78 g) in tetrahydrofuran (28.0 ml) was added
di-tert-butyl dicarbonate (1.99 ml) and the solution was stirred at
room temperature for 20 hours. The solvent was removed by
evaporation and the residue was chromatographed on silica gel
(eluent: hexane/ethyl acetate=1/1) to give tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hyd
roxyethyl]carbamate (1.57 g) as a pale yellow solid.
MS m/z: 443 (M+Na.sup.+)
Preparation 25
A solution of (2S)-2-[(4-(benzyloxy)phenoxy)methyl]-oxirane (1.19
g) and (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (1.33 g)
in ethanol (13 ml) was refluxed for 20 hours. After cooling to room
temperature, the solvent was removed by evaporation and the residue
was chromatographed on silica gel (eluent:
chloroform/methanol=98/2) to give
(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3
-(4-nitrophenyl)-1-propanol (2.04 g) as a yellow gum.
MS m/z: 543 (MH.sup.+)
Preparation 26
A solution of
(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3
-(4-nitrophenyl)-1-propanol (2.00 g) in a mixed solvent of ethanol
(7.5 ml) and 1,4-dioxane (7.5 ml) was added dropwise to a stirred
suspension of iron powder (2.00 g) and ammonium chloride (0.24 g)
in a mixed solvent of ethanol (5 ml) and water (5 ml) at 85.degree.
C. over 10 minutes and the resulting mixture was stirred at the
same temperature for 30 minutes. The insoluble solid was filtered
off and washed with dioxane, and the filtrate was concentrated in
vacuo. The residue was partitioned between saturated aqueous sodium
hydrogencarbonate solution and ethyl acetate. The organic layer was
separated, washed with brine, dried over magnesium sulfate, and
evaporated to give
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydr
oxypropyl]-amino]-1-propanol (1.90 g) as a pale yellow oil.
MS m/z: 513 (MH.sup.+)
Preparation 27
To a 0.024 M solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropy
l]carbamate in 1,2-dichloromethane (15 ml) was added
N,O-bis(trimethylsilyl)acetamide (270 .mu.l) and stirred overnight
at ambient temperature. Evaporation of the solvent gave a residue,
which was purified by column chromatography on silica gel (eluent:
0-33% ethyl acetate in hexane) to give tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-[(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-
2-[(trimethylsilyl)oxy]propylcarbamate (190 mg) as a yellow
oil.
NMR (DMSO-d.sub.6, .delta.): 0.02 (9H, s), 0.09 (9H, s), 1.42 (9H,
s), 2.55-2.70 (2H, m), 3.20-4.35 (8H, m), 4.87 (2H, s), 6.49 (2H,
d, J=8.4 Hz), 6.75-7.00 (5H, m), 7.20-7.35 (2H, m)
(+)-APCI MS m/z: 461 (M-CO.sub.2 -tert-butyl+H).sup.+
EXAMPLE 1
To an ice-cooled solution of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino
]-1-propanol (83 mg) in dichloromethane (0.8 ml) was added dropwise
ethyl isocyanate (0.016 ml). The mixture was stirred at the same
temperature for 1.5 hours and partitioned between chloroform and
saturated sodium bicarbonate solution. The organic layer was
separated, washed with brine, dried over magnesium sulfate, and
filtered. The filtrate was concentrated and the residue was
purified by column chromatography (silica gel, chloroform/methanol)
to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-N'-ethylurea (84 mg) as a white amorphous powder.
NMR (CDCl.sub.3, .delta.): 1.12 (3H, t, J=7 Hz), 2.51 (1H, dd, J=14
and 9 Hz), 2.63-3.37 (6H, m), 3.37-4.02 (7H, m), 4.85 (1H, t, J=6
Hz), 6.46 (1H, s), 6.81 (2H, d, J=9 Hz), 6.86-7.40 (12H, m)
MS m/z: 478 (M.sup.+ +1)
EXAMPLE 2
A solution of
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-N'-ethylurea (73 mg) in methanol (1.5 ml) was
hydrogenated (1 atm) over 10% palladium on carbon (11 mg) at room
temperature for 12 hours. After the catalyst was filtered off, the
filtrate was concentrated and the residue was purified by column
chromatography (silica gel, chloroform/methanol) followed by
recrystallization from ehtanol/hexane to give
N-ethyl-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-pr
opyl]phenyl]urea (38 mg) as a white powder.
mp: 129-130.degree. C.
IR (KBr): 1678, 1637, 1597, 1558 cm.sup.-1
NMR (CD.sub.3 OD, .delta.): 1.14 (3H, t, J=7 Hz), 2.62-3.16 (5H,
m), 3.21 (2H, q, J=7 Hz), 3.45 (1H, dd, J=1 and 6 Hz), 3.63 (1H,
dd, J=11 and 4 Hz), 3.90-4.20 (3H, m), 6.84-7.36 (9H, m)
MS m/z: 388 (M.sup.+ +1)
EXAMPLE 3
To an ice-cooled solution of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino
]-1-propanol (76 mg) in dichloromethane (0.8 ml) was added dropwise
phenyl isocyanate (0.022 ml), and the mixture was stirred at the
same temperature for 40 minutes. One drop of 28% ammonia solution
was added to the mixture, the mixture was concentrated, and the
residue was purified by column chromatography (silica gel,
chloroform/methanol) to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxy
propyl]phenyl]-N'-phenylurea (89 mg) as a white amorphous
powder.
NMR (CDCl.sub.3, .delta.): 2.48 (1H, dd, J=13 and 8 Hz), 2.63-3.22
(4H, m), 3.38-4.02 (7H, m), 6.66-7.43 (21H, m)
MS m/z: 526 (M.sup.+ +1)
EXAMPLE 4
The following compounds were obtained according to a similar manner
to that of Example 2. (1)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-phenylurea
IR (KBr): 3440-2921, 1641, 1596, 1560, 1498, 1315, 1238
cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.50-2.64 (5H, m), 3.10-3.20 (2H, m),
3.80-4.00 (3H, m), 4.50-4.60 (1H, m), 4.93 (1H, d, J=4.2 Hz),
6.85-7.00 (4H, m), 7.05-7.15 (2H, m), 7.25-7.50 (8H, m), 8.57 (1H,
s), 8.63 (1H, s)
MS m/z: 436 (M.sup.+ +1) (2)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]benzamide
mp: 124-125.degree. C.
IR (KBr): 1655, 1599, 1529 cm.sup.-1
NMR (CD.sub.3 OD, .delta.): 2.58-3.05 (5H, m), 3.43 (1H, dd, J=11
and 6 Hz), 3.60 (1H, dd, J=11 and 4 Hz), 3.83-4.15 (3H, m),
6.80-7.00 (3H, m), 7.12-7.35 (4H, m), 7.40-7.70 (5H, m), 7.83-8.01
(2H, m)
MS m/z: 421 (M.sup.+ +1) (3)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-4-methoxybenzamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.60-3.12 (5H, m),
3.45 (1H, dd, J=11 and 6 Hz), 3.64 (1H, dd, J=11 and 4 Hz), 3.89
(3H, s), 3.90-4.20 (3H, m), 6.80-7.12 (5H, m), 7.12-7.40 (4H, m),
7.60 (2H, d, J=8 Hz), 7.91 (2H, d, J=9 Hz)
MS m/z: 451 (M.sup.+ +1) (4)
4-Chloro-N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]pro
pyl]phenyl]benzamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.66-3.15 (5H, m),
3.47 (1H, dd, J=11 and 6 Hz), 3.66 (1H, dd, J=11 and 4 Hz),
3.86-4.20 (3H, m), 6.82-7.06 (3H, m), 7.13-7.38 (4H, m), 7.48 (2H,
d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 7.90 (2H, d, J=9 Hz)
MS m/z: 455 (M.sup.+ +1) (5)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-3-methoxybenzamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.60-3.10 (5H, m),
3.44 (1H, dd, J=11 and 6 Hz), 3.63 (1H, dd, J=11 and 4 Hz), 3.88
(3H, s), 3.88-4.15 (3H, m), 6.80=7.74 (13H, m)
MS m/z: 451 (M.sup.+ +1) (6)
3-Chloro-N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]pro
pyl]phenyl]benzamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.58-3.11 (5H, m),
3.44 (1H, dd, J=11 and 6 Hz), 3.63 (1H, dd, J=11 and 4 Hz),
3.85-4.18 (3H, m), 6.80-8.02 (13H, m)
MS m/z: 455 (M.sup.+ +1) (7)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-1-naphthamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.60-3.10 (5H, m),
3.45 (1H, dd, J=11 and 6 Hz), 3.62 (1H, dd, J=11 and 4 Hz),
3.82-4.22 (3H, m), 6.82-8.33 (16H, m)
MS m/z: 471 (M.sup.+ +1) (8)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-2-naphthamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.72-3.23 (5H, m),
3.58 (1H, dd, J=11 and 6 Hz), 3.76 (1H, dd, J=11 and 4 Hz),
3.95-4.30 (3H, m), 6.90-8.25 (15H, m), 8.59 (1H, s)
MS m/z: 471 (M.sup.+ +1) (9)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-1H-pyrrole-2-carboxamide
NMR (CDCl.sub.3 --CD.sub.3 OD(1:1), .delta.): 2.76-3.30 (5H, m),
3.63 (1H, dd, J=11 and 6 Hz), 3.82 (1H, dd, J=11 and 4 Hz),
4.03-4.37 (3H, m), 6.39-6.49 (1H, m), 6.98-7.29 (5H, m), 7.29-7.57
(4H, m), 7.76 (2H, d, J=8 Hz)
MS m/z: 410 (M.sup.+ +1) (10)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]nicotinamide
NMR (DMSO-d.sub.6, .delta.): 2.53-3.05 (5H, m), 3.29 (1H, dd, J=11
and 6 Hz), 3.44 (1H, dd, J=11 and 4 Hz), 3.76-4.10 (3H, m),
6.80-7.04 (3H, m), 7.13-7.38 (4H, m), 7.57 (1H, dd, J=8 and 5 Hz),
7.70 (2H, d, J=8 Hz), 8.29 (1H, ddd, J=8, 2 and 2 Hz), 8.76 (1H,
dd, J=5 and 2 Hz), 9.11 (12H, d, J=2 Hz), 10.45 (1H, br s)
MS m/z: 422 (M.sup.+ +1) (11)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N-methylbenzamide
mp: 115-116.degree. C.
IR (KBr): 1637, 1601 cm.sup.-1
NMR (CDCl.sub.3, .delta.): 2.53-3.00 (5H, m), 3.32 (1H, dd, J=11
and 5 Hz), 3.47 (3H, s), 3.58 (1H, dd, J=11 and 4 Hz), 3.84-4.10
(3H, m), 6.80-7.38 (14H, m)
MS m/z: 435 (M.sup.+ +1) (12)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-[4-hydroxy-3-(hydroxymethyl)phen
oxy]propyl]amino]propyl]phenyl]-benzamide
IR (KBr): 3500-3000, 1641, 1600, 1446, 1029 cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.90-3.10 (3H, m), 3.30-3.60 (4H, m),
3.80-4.00 (2H, m), 4.10-4.30 (1H, m), 4.71 (2H, s), 6.67 (2H, s),
6.93 (1H, s), 7.10-7.90 (9H, m)
MS m/z: 467 (M.sup.+ +1)
EXAMPLE 5
To an ice-cooled mixture of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino
]-1-propanol (63 mg) and pyridine (25 .mu.l) in dichloromethane
(0.6 ml) was added dropwise benzoyl chloride (22 .mu.l), and the
mixture was stirred at room temperature for more than 2 hours. The
mixture was partitioned between chloroform-methanol and water. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated and
the residue was purified by column chromatography (silica gel,
chloroform/methanol) to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]benzamide (80 mg) as a white amorphous powder.
NMR (CDCl.sub.3, .delta.): 2.56 (1H, dd, J=14 and 9 Hz), 2.72-3.28
(4H, m), 3.44-4.04 (7H, m), 6.83 (2H, d, J=9 Hz), 6.86-7.03 (1H,
m), 7.14 (2H, d, J=8 Hz), 7.20-7.40 (7H, m), 7.40-7.63 (5H, m),
7.78-7.96 (2H, m), 7.80 (1H, br s)
MS m/z: 511 (M.sup.+ +1)
EXAMPLE 6
To a mixture of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino
]-1-propanol (77 mg) and benzoic acid (28 mg) in
N,N-dimethylformamide (0.8 ml) was added
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57
mg), and the mixture was stirred at room temperature for 20 hours.
The mixture was partitioned between hexane-ethyl acetate and water.
The organic layer was separated, washed successively with water and
brine, dried over magnesium sulfate, and filtered. The filtrate was
concentrated to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino)-3-hydroxyp
ropyl]phenyl]-benzamide (95 mg) as a white amorphous powder.
NMR (CDCl.sub.3, .delta.): 2.56 (1H, dd, J=14 and 9 Hz), 2.71-3.28
(4H, m), 3.42-4.03 (7H, m), 6.82 (2H, d, J=9 Hz), 6.88-7.02 (1H,
m), 7.14 (2H, d, J=8 Hz), 7.18-7.38 (7H, m), 7.38-7.65 (5H, m),
7.77-7.97 (2H, m), 7.80 (1H, br s)
MS m/z: 511 (M.sup.+ +1)
EXAMPLE 7
The following compounds were obtained according to a similar manner
to that of Example 6. (1)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-4-methoxybenzamide
NMR (CDCl.sub.3, .delta.): 2.55 (1H, dd, J=13 and 9 Hz), 2.71-3.26
(4H, m), 3.45-4.02 (7H, m), 3.86 (3H, s), 6.73-7.38 (14H, m), 7.53
(2H, d, J=8 Hz), 7.77 (1H, br s), 7.84 (2H, d, J=9 Hz)
MS m/z: 541 (M.sup.+ +1) (2)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-4-chlorobenzamide
NMR (CDCl.sub.3, .delta.): 2.56 (1H, dd, J=13 and 9 Hz), 2.70-3.28
(4H, m), 3.43-4.05 (7H, m), 6.73-7.03 (3H, m), 7.13 (2H, d, J=9
Hz), 7.17-7.36 (7H, m), 7.46 (2H, d, J=9 Hz), 7.52 (2H, d, J=8 Hz),
7.77 (1H, br s), 7.81 (2H, d, J=9 Hz)
MS m/z: 545 (M.sup.+ +1) (3)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-3-methoxybenzamide
NMR (CDCl.sub.3, .delta.): 2.56 (1H, dd, J=14 and 9 Hz), 2.70-3.30
(4H, m), 3.42-4.03 (7H, m), 3.87 (3H, s), 6.73-7.62 (18H, m), 7.80
(1H, br s)
MS m/z: 541 (M.sup.+ +1) (4)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-3-chlorobenzamide
NMR (CDCl.sub.3, .delta.): 2.56 (1H, dd, J=14 and 9 Hz), 2.72-3.30
(4H, m), 3.42-4.05 (7H, m), 6.74-7.93 (19H, m)
MS m/z: 545 (M.sup.+ +1) (5)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl phenyl]-1-naphthamide
NMR (CDCl.sub.3, .delta.): 2.58 (1H, dd, J=14 and 9 Hz), 2.72-3.28
(4H, m), 3.28-4.03 (7H, m), 6.72-8.04 (21H, m), 8.26-8.45 (1H,
m)
MS m/z: 561 (M.sup.+ +1) (6)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-2-naphthamide
NMR (CDCl.sub.3, .delta.): 2.57 (1H, dd, J=14 and 9 Hz), 2.72-3.30
(4H, m), 3.42-4.04 (7H, m), 6.72-8.07 (21H, m), 8.38 (1H, s)
MS m/z: 561 (M.sup.+ +1)
EXAMPLE 8
To a mixture of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino
]-1-propanol (79 mg) and pyrrole-2-carboxylic acid (26 mg) in
dichloromethane (0.8 ml) was added
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (59
mg), and the mixture was stirred at room temperature for 47 hours.
The mixture was partitioned between ethyl acetate and water. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated, and
the residue was purified by column chromatography (silica gel,
hexane/ethyl acetate) to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxyp
ropyl]-phenyl]-1H-pyrrole-2-carboxamide (48 mg) as a white
amorphous powder.
NMR (CDCl.sub.3, .delta.): 2.53 (1H, dd, J=14 and 9 Hz), 2.68-3.28
(4H, m), 3.42-4.04 (7H, m), 6.23-6.34 (1H, m), 6.65-6.75 (1H, m),
6.75-7.05 (4H, m), 7.10 (2H, d, J=8 Hz), 7.17-7.41 (7H, m), 7.49
(2H, d, J=8 Hz).sub.1 7.58 (1H, br s), 9.56 (1H, br s)
MS m/z: 500 (M.sup.+ +1)
EXAMPLE 9
The following compound was obtained according to a similar manner
to that of Example 5.
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypr
opyl]phenyl]nicotinamide
NMR (CDCl.sub.3, .delta.): 2.56 (1H, dd, J=14 and 9 Hz), 2.70-3.30
(4H, m), 3.42-4.04 (7H, m), 6.72-7.05 (3H, m), 7.14 (2H, d, J=8
Hz), 7.18-7.38 (7H, m), 7.44 (1H, dd, J=8 and 5 Hz), 7.54 (2H, d,
J=8 Hz), 7.98 (1H, br s), 8.21 (1H, ddd, J=8, 2 and 2 Hz), 8.76
(1H, dd, J=5 and 2 Hz), 9.08 (1H, d, J=2 Hz)
MS m/z: 512(M.sup.+ +1)
EXAMPLE 10
To an ice-cooled solution of
N-[4-[(2S)-3-acetoxy-2-[N-[(2S)-2-acetoxy-3-phenoxypropyl]-N-benzylamino]p
ropyl]-phenyl]benzamide (107 mg) in tetrahydrofuran (1.1 ml) was
added sodium hydride (60% in oil, 17 mg), and the mixture was
stirred at the same temperature for 30 minutes. To the mixture was
added iodomethane (25 .mu.l), and the mixture was stirred at room
temperature for 1.5 hours before being partitioned between ethyl
acetate and water. The organic layer was separated, washed with
brine, dried over magnesium sulfate, and filtered. The filtrate was
concentrated and the residue was dissolved in methanol (1.1
ml)-1,4-dioxane (1.1 ml), then treated with 1N sodium hydroxide
(0.5 ml) at room temperature for 1.5 hours. The mixture was
concentrated and partitioned between ethyl acetate and water. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated and
the residue was purified by column chromatography (silica gel,
hexane/ethyl acetate) to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxy
propyl]phenyl]-N-methylbenzamide (55 mg) as a white amorphous
powder.
NMR (CDCl.sub.3, .delta.): 2.49 (1H, d, J=14 and 9 Hz), 2.65-3.22
(4H, m), 3.34-3.72 (3H, m), 3.47 (3H, s), 3.72-4.04 (4H, m),
6.74-7.40 (19H, m)
MS m/z: 525 (M.sup.+ +1)
EXAMPLE 11
To a 0.5 M solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropy
l)carbamate in dichloroethane (40 .mu.l) were added successively
2.0 M solution of N,O-bis(trimethylsilyl)-acetamide in
1-methyl-2-pyrrolidinone (10 .mu.l), 1.0 M solution of ethyl
isocyanate in 1-methyl-2-pyrrolidinone (24 .mu.l), and 0.1 M
solution of N-ethyldiisopropylamine in 1-methyl-2-pyrrolidinone (20
.mu.l) at room temperature. After shaking at room temperature for
30 minutes, the solution was treated with 500 .mu.l of
trifluoroacetic acid/water (95/5) at 50.degree. C. for 30 minutes.
The mixture was evaporated and the residue was purified by reverse
phase HPLC (0-100% acetonitrile in water (containing 0.1%
trifluoroacetic acid)) to give
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-propylurea trifluoroacetate (5.51 mg) as a pale yellow
oil.
MS m/z: 402(M.sup.+ +1)
EXAMPLE 12
The following compounds were obtained according to a similar manner
to that of Example 11. (1)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-isopropylurea trifluoroacetate
MS m/z: 402 (M.sup.+ +1) (2)
N-(2-Chlorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 470 (M.sup.+ +1) (3)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(3-nitrophenyl)urea trifluoroacetate
MS m/z: 450 (M.sup.+ +1) (4)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(3-methoxyphenyl)urea trifluoroacetate
MS m/z: 466 (M.sup.+ +1) (5)
N-Benzoyl-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]p
ropyl]phenyl]urea trifluoroacetate
MS m/z: 464 (M.sup.+ +1) (6)
N-Cyclohexyl-N'-(4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amin
o]propyl]phenyl]urea trifluoroacetate
MS m/z: 442 (M.sup.+ +1) (7)
N-(3-Fluorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 454 (M.sup.+ +1) (8)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-4-methoxyphenyl)urea trifluoroacetate
MS m/z: 466 (M.sup.+ +1) (9)
N-(2-Chloroethyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl
)amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 422 (M.sup.+ +1) (10)
N-(3-Bromophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl
]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 515 (M.sup.+ +1) (11)
N-(4-Bromophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl
]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 515 (M.sup.+ +1) (12)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(3-methylphenyl)urea trifluoroacetate
MS m/z: 450 (M.sup.+ +1) (13)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(2-methylphenyl)urea trifluoroacetate
MS m/z: 450 (M.sup.+ +1) (14)
N-(3-Acetylphenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 478 (M.sup.+ +1) (15)
N-(3-Cyanophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl
]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 461 (M.sup.+ +1) (16) Ethyl
[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]anili
no]carbonyl]amino]-acetate trifluoroacetate
MS m/z: 446 (M.sup.+ +1) (17)
N-(2,3-Dichlorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxyp
ropyl]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 505 (M.sup.+ +1) (18)
N-[4-Chloro-3-(trifluoromethyl)phenyl]-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hy
droxy-3-phenoxypropyl]amino]-propyl]phenyl]urea
trifluoroacetate
MS m/z: 538 (M.sup.+ +1) (19)
N-(2-Fluorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l)amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 454 (M.sup.+ +1) (20)
N-(4-Fluorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 454 (M.sup.+ +1) (21)
N-(3-Chlorophenyl)-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropy
l]amino]propyl]phenyl]urea trifluoroacetate
MS m/z: 470 (M.sup.+ +1) (22)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(2-nitrophenyl)urea trifluoroacetate
MS m/z: 481 (M.sup.+ +1) (23)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-(4-nitrophenyl)urea trifluoroacetate
MS m/z: 481 (M.sup.+ +1) (24)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-[2-(trifluoromethyl)phenyl]urea trifluoroacetate
MS m/z: 504 (M.sup.+ +1) (25)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-[3-(trifluoromethyl)phenyl]urea trifluoroacetate
MS m/z: 504 (M.sup.+ +1) (26)
N-Benzyl-N'-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]pr
opyl]phenyl]urea trifluoroacetate
MS m/z: 450 (M.sup.+ +1)
EXAMPLE 13
To an ice-cooled solution of
(2S)-1-phenoxy-3-[N-[(2S)-2-(4-aminophenyl)-1-(hydroxymethyl)ethyl]-N-benz
ylamino]-2-propanol (95 mg) and pyridine (37 mg) in dichloromethane
(1 ml) was added dropwise acetic anhydride (26.2 mg). The mixture
was stirred at the same temperature for 1 hour and partitioned
between chloroform and saturated sodium bicarbonate solution. The
organic layer was separated, washed with brine, dried over
magnesium sulfate, and filtered. The filtrate was concentrated. A
solution of the residue in methanol (1 ml) was hydrogenated (1 atm)
over 10% palladium on carbon (15 mg) at room temperature for 2
hours. After the catalyst was filtered off, the filtrate was
concentrated and the residue was purified by column chromatography
(silica gel, chloroform/methanol) to give
(2S)-1-phenoxy-3-[[(2S)-2-(4-acetamidophenyl)-1-(hydroxymethyl)ethyl]amino
]-2-propanol (50 mg) as a colorless form.
IR (KBr): 3300-3200, 1664, 1602, 1407, 1243 cm.sup.-1
NMR (CDCl.sub.3, .delta.): 2.11 (3H, s), 2.70-3.20 (5H, m),
3.40-3.70 (2H, m), 3.97 (2H, d, J=4.6 Hz), 4.10 (1H, m), 6.80-6.90
(3H, m), 7.10-7.30 (4H, m), 7.48 (2H, d, J=8.5 Hz)
MS m/z: 359 (M.sup.+ +1)
EXAMPLE 14
The following compound was obtained according to a similar manner
to that of Example 13.
(2S)-1-Phenoxy-3-[[(2S)-2-(4-ureidophenyl)-1-(hydroxymethyl)ethyl]amino]-2-
propanol
IR (KBr): 3500-3200, 1658, 1589, 1548, 1243 cm.sup.-1
NMR (CDCl.sub.3, .delta.): 2.65-3.00 (5H, m), 3.30-3.80 (2H, m),
3.90-4.05 (3H, m), 6.90-7.40 (9H, m)
MS m/z: 391 (M.sup.+ +1)
EXAMPLE 15
Under nitrogen, a solution of
(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N'-phenylurea
hydrochloride (150 mg), (R)-3-chlorostyrene oxide (56 mg) and
N,N-diisopropylethylamine (0.17 ml) in ethanol (5 ml) was refluxed
for 28 hours. The mixture was evaporated in vacuo. The residue was
purified by column chromatography on silica gel
(chloroform:methanol=100:1) to give
N-[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxyprop
yl]phenyl]-N'-phenylurea (45 mg) as a colorless form.
IR (KBr): 3500-3000, 1648, 1540, 1513, 1313, 1230 cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.60-2.90 (5H, m), 3.40-3.60 (2H, m),
4.60-4.70 (1H, m), 6.90-7.40 (13H, m)
MS m/z: 440 (M.sup.+ +1)
EXAMPLE 16
The following compounds were obtained according to a similar manner
to that of Example 15. (1)
N-[4-[(2S)-2-[[(2S)-3-(1H-Indol-4-yloxy)-2-hydroxypropyl]amino]-3-hydroxyp
ropyl]phenyl]-N'-phenylurea
IR (KBr): 3400-3000, 1644, 1540, 1438, 1228, 1060 cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.60-3.10 (5H, m), 3.30-3.60 (2H, m),
4.00-4.10 (3H, m), 6.40-6.60 (2H, m), 6.90-7.45 (12H, m)
MS m/z: 475 (M.sup.+ +1) (2)
N-[4-[(2S)-2-[[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino]-3-hydro
xypropyl]phenyl]-N'-phenylurea
IR (KBr): 3300-3000, 1637, 1598, 1554, 1504, 1207 cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.60-3.10 (5H, m), 3.40-3.70 (2H, m),
4.05-4.40 (3H, m), 6.90-7.50 (15H, m), 8.3 (1H, d, J=7 Hz)
MS m/z: 525 (M.sup.+ +1) (3)
N-[4-[(2S)-2-[[(2S)-3-(4-Fluorophenoxy)-2-hydroxypropyl]amino]-3-hydroxypr
opyl]phenyl]-N'-phenylurea
IR (KBr): 3300-3000, 1637, 1598, 1554, 1504, 1207 cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.50-2.95 (5H, m), 3.30-3.65 (2H, m),
3.90-4.10 (3H, m), 6.90-7.50 (9H, m)
MS m/z: 454 (M.sup.+ +1) (4)
N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-3-[4-(benzyloxy)-3-(hydroxymethyl)phenoxy]-
2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide
NMR (CDCl.sub.3, .delta.): 2.30-3.00 (6H, m), 3.05-3.20 (1H, m),
3.40-4.00 (7H, m), 4.60 (2H, d, J=6.4 Hz), 5.00 (2H, s), 6.67 (1H,
dd, J=3, 9 Hz), 6.80-6.85 (2H, m), 7.10-7.60 (18H, m), 7.80-7.90
(3H, m)
MS m/z: 647 (M.sup.+ +1)
EXAMPLE 17
To a solution of 10% hydrogen chloride in methanol was added
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino)propyl]pheny
l]-N'-phenylurea (70 mg) and stirred for 15 minutes. The reaction
mixture was concentrated and followed by recrystallization from
ethanol to give
N-[4-[(2S)-3-hydroxy-2-([(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-N'-phenylurea hydrochloride (38 mg) as a white powder.
IR (KBr): 3330-2950, 1697, 1600, 1556, 1498, 1319, 1238
cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.70-3.35 (4H, m), 3.40-3.70 (3H, m)
4.00 (2H, d, J=5.0 Hz), 4.15-4.30 (1H, m), 5.41 (1H, s), 5.87 (1H,
d, J=4.8 Hz), 6.90-7.00 (4H, m), 7.15-7.50 (10H, m), 9.06 (1H, s),
9.07 (1H, s)
MS m/z: 436 (M.sup.+ +1)
EXAMPLE 18
To a solution of ethyl
2-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl
)amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate
(10.0 mg) in 1,2-dichloroethane (100 .mu.l) was added
trifluoroacetic acid (100 .mu.l) and the solution was stirred at
room temperature for 30 minutes. The solvent was removed by
evaporation to give ethyl
2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]-carbonyl]amino]benzoate trifluoroacetate (10.3 mg) as a
white foam.
MS m/z: 508 (MH.sup.+)
EXAMPLE 19
The following compounds were obtained according to a similar manner
to that of Example 18. (1) Ethyl
3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-hydroxy-3-phenoxypropyl]amino]propyl]phen
yl]amino]carbonyl]-amino]benzoate trifluoroacetate
MS m/z: 508 (MH.sup.+) (2) Ethyl
4-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]-amino]benzoate trifluoroacetate
MS m/z: 508 (MH.sup.+)
EXAMPLE 20
To a solution of tert-butyl
N-[(1S)-1-[4-[[[(2-nitrophenyl)amino]carbonyl]amino]benzyl]-2-(trimethylsi
lyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamate
(95.0 mg) in methanol (2.9 ml) was added 10% palladium on activated
carbon (50% wet, 95 mg) and the mixture was hydrogenated at 1 atm
for 1 hour. The catalyst was filtered off and the filtrate was
concentrated in vacuo to give tert-butyl
N-[(1S)-1-[4-[[[(2-aminophenyl)amino]carbonyl]amino]benzyl]-2-hydroxyethyl
]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (75.3 mg) as a brown
solid.
MS (ESI) m/z: 573 (M+Na.sup.+)
EXAMPLE 21
The following compounds were obtained according to a similar manner
to that of Example 20. (1) tert-Butyl
N-[(1S)-1-[4-[[[(3-aminophenyl)amino]-carbonyl]amino]benzyl]-2-hydroxyethy
l]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate
MS (ESI) m/z: 573 (M+Na.sup.+) (2) tert-Butyl
N-[(1S)-1-[4-[[[(4-aminophenyl)amino]-carbonyl]amino]benzyl]-2-hydroxyethy
l]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate
MS (ESI) m/z: 573 (M+Na.sup.+)
EXAMPLE 22
To a solution of tert-butyl
N-[(1S)-1-[4-[[[(2-aminophenyl)amino]carbonyl]amino]benzyl]-2-hydroxyethyl
]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (20.0 mg) in
1,2-dichloroethane (200 .mu.l) were added successively 1.0 M
solution of pyridine in 1,2-dichloroethane (54.5 .mu.l) and 1.0 M
solution of methanesulfonyl chloride in 1,2-dichloroethane (43.6
.mu.l) at room temperature. After stirring for 2 hours, the solvent
was removed by evaporation and the residue was purified by a
recycling preparative high pressure liquid chromatography equipped
with a gel permeation chromatography column (eluent: chloroform) to
give a light brown solid. The solid was dissolved in
1,2-dichloroethane (200 .mu.l). To the solution was added
trifluoroacetic acid (200 .mu.l) and the mixture was stirred for 30
minutes. The solvent was removed by evaporation to give
N-[2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl
]phenyl]amino]-carbonyl]amino]phenyl]methanesulfonamide
trifluoroacetate (20.3 mg) as a light brown solid.
MS m/z: 529 (MH.sup.+)
EXAMPLE 23
The following compounds were obtained according to a similar manner
to that of Example 22. (1) Methyl
N-[2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl
]phenyl]amino]carbonyl]-amino]phenyl]carbamate trifluoroacetate
MS m/z: 509 (MH.sup.+) (2)
N-[3-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl
]phenyl]amino]carbonyl]-amino]phenyl]methanesulfonamide
trifluoroacetate
MS m/z: 529 (MH.sup.+) (3) Methyl
N-[3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl
]phenyl]amino]carbonyl]-amino]phenyl]carbamate trifluroacetate
MS m/z: 509 (MH.sup.+) (4)
N-[4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino)propyl
]phenyl]amino]carbonyl]-amino]phenyl]methanesulfonamide
trifluoroacetate
MS m/z: 529 (MH.sup.+) (5) Methyl
N-[4-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl
]phenyl]amino]carbonyl]-amino]phenyl]carbamate trifluoroacetate
MS m/z: 509 (MH.sup.+)
EXAMPLE 24
To a solution of ethyl
3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl
]amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate
(204 mg) in 1,2-dichloroethane (2.0 ml) was added trifluroacetic
acid (2.0 ml) and the solution was stirred at room temperature for
1 hour. The solvent was removed by evaporation and the residue was
dissolved in ethyl acetate (10 ml). The solution was washed with
aqueous saturated sodium bicarbonate solution (5 ml.times.1) and
brine (10 ml.times.1) successively, dried over magnesium sulfate,
and evaporated to give ethyl
3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]amino]-benzoate (148 mg) as a white solid.
EXAMPLE 25
The following compound was obtained according to a similar manner
to that of Example 24.
Ethyl
4-[[[[4-[(2S)-3-hydroxy-2-[((2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino)carbonyl]amino]-benzoate
EXAMPLE 26
To a solution of ethyl
3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]-amino]carbonyl]amino]benzoate (148 mg) in ethanol (2.0 ml)
was added 1N sodium hydroxide solution (292 .mu.l) and the solution
was refluxed for 4 hours. An additional portion of 1N sodium
hydroxide solution (58.3 .mu.l) was added and the whole was
refluxed for 3 hours. After cooling to room temperature, the
solvent was removed by evaporation to give sodium
3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]amino)-benzoate (158 mg) as a white solid.
MS m/z: 502 (MH.sup.+)
EXAMPLE 27
The following compound was obtained according to a similar manner
to that of Example 26.
Sodium
4-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl)amino]carbonyl]amino]-benzoate
MS m/z: 502 (MH.sup.+)
EXAMPLE 28
To a solution of sodium
3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]-amino]carbonyl]amino]benzoate (50.0 mg) in a mixed solvent of
tetrahydrofuran (1.0 ml) and water (1.0 ml) was added 1N sodium
hydroxide solution (99.7 .mu.l). To the solution was added
di-tert-butyl dicarbonate (27.5 .mu.l) at room temperature and the
mixture was stirred for 2 hours. An additional portion of
di-tert-butyl dicarbonate (27.5 .mu.l) was added and the mixture
was stirred for 30 minutes. To the mixture was added pH 4.0 buffer
solution (10 ml) and the resulting suspension was extracted with
ethyl acetate (30 ml.times.1). The organic layer was separated and
washed with brine (10 ml.times.1), dried over magnesium sulfate,
and evaporated to give
3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl
]amino]-3-hydroxypropyl]phenyl]-amino]carbonyl]amino]benzoic acid
(47.3 mg) as a yellow solid.
EXAMPLE 29
The following compound was obtained according to a similar manner
to that of Example 28.
4-[[[[4-[(2S)-2-[N-(tert-Butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]
amino]-3-hydroxypropyl]phenyl]-amino]carbonyl]amino]benzoic
acid
MS (negative) m/z: 578 (M-H.sup.+)
EXAMPLE 30
To a solution of
3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl
]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]amino]benzoic acid
(10.0 mg) in N,N-dimethylformamide (100 .mu.l) were added
successively a 1.0 M solution of 1-hydroxybenzotriazole hydrate in
N,N-dimethylformamide (20.7 .mu.l) and a 1.0 M solution of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in
1,2-dichloroethane (20.7 .mu.l) at room temperature. To the
solution was added methylamine hydrochloride (1.4 mg) and the
mixture was stirred for 4 hours. The reaction mixture was diluted
with ethyl acetate (10 ml) and washed with water (10 ml.times.1)
and brine (10 ml.times.1) successively, dried over magnesium
sulfate, and evaporated to give a pale yellow paste. The crude
product was purified by a recycling preparative high pressure
liquid chromatography equipped with a gel permeation chromatography
column (eluent: chloroform) to give tert-butyl
(1S)-2-hydroxy-1-[4-[[[[3-(methylcarbamoyl)phenyl]amino]carbonyl]amino]ben
zyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (7.2 mg) as
a pale yellow solid.
EXAMPLE 31
The following compounds were obtained according to a similar manner
to that of Example 30. (1) tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[[[3-(propylcar
bamoyl)phenyl]amino]-carbonyl]amino]benzyl]ethyl]carbamate (2)
tert-Butyl
N-[(1S)-1-[4-[[[[3-(dimethylcarbamoyl)-phenyl]amino]carbonyl]amino]benzyl]
-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (3)
tert-Butyl
N-[(1S)-2-hydroxy-1-[4-[[[[4-(methylcarbamoyl)phenyl]amino]carbonyl]amino]
benzyl]-ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (4)
tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[[[4-(propylcar
bamoyl)phenyl]amino]-carbonyl]amino]benzyl]ethyl]carbamate (5)
tert-Butyl
N-[(1S)-1-[4-[[[[4-(dimethylcarbamoyl)-phenyl]amino]carbonyl]amino]benzyl]
-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate
EXAMPLE 32
To a solution of tert-butyl
N-[(1S)-2-hydroxy-1-[4-[[[[3-(methylcarbamoyl)phenyl]amino)carbonyl]amino]
benzyl]-ethyl]-N-[(2S)-2-hydroxy-3-phenoxypopyl]carbamate (7.2 mg)
in a mixed solvent of 1,2-dichloroethane (100 .mu.l) and methanol
(25 .mu.l) was added trifluoroacetic acid (100 .mu.l) and the
mixture was stirred at room temperature for 3 hours. The solvent
was removed by evaporation to give
3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]p
henyl]amino]carbonyl]amino]-N-methylbenzamide trifluroacetate (7.2
mg) as a pale yellow foam.
MS m/z: 493 (MH.sup.+)
EXAMPLE 33
The following compounds were obtained according to a similar manner
to that of Example 32. (1)
3-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]-amino]-N-propylbenzamide trifluroacetate
MS m/z: 521 (MH.sup.+) (2)
3-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]-amino]-N,N-dimethylbenzamide
trifluoroacetate
MS m/z: 507 (MH.sup.+) (3)
4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-pyhenoxypropyl]amino]propyl]p
henyl]amino]carbonyl]-amino]-N-methylbenzamide trifluoroacetate
NMR (DMSO-d.sub.6, .delta.): 2.76 (3H, d, J=4.5 Hz), 2.86-4.30
(10H, m), 5.41 (1H, br), 5.83 (1H, br), 6.94-7.00 (3H, m), 7.21
(2H, d, J=8.5 Hz), 7.28-7.36 (2H, m), 7.44 (2H, d, J=8.5 Hz), 7.52
(2H, d, J=8.8 Hz), 7.77 (2H, d, J=8.8 Hz), 8.32 (2H, br), 8.69 (1H,
br), 9.11 (1H, br s), 9.31 (1H, br s)
MS m/z: 493 (MH.sup.+) (4)
4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]-amino]-N-propylbenzamide trifluoroacetate
NMR (DMSO-d.sub.6, .delta.): 0.88 (3H, t, J=7.4 Hz), 1.43-1.58 (2H,
m), 2.80-4.20 (10H, m), 5.44 (1H, br), 5.86 (1H, br), 6.94-7.00
(3H, m), 7.21 (2H, d, J=8.5 Hz), 7.28-7.36 (2H, m), 7.44 (2H, d,
J=8.5 Hz), 7.51 (2H, d, J=8.7 Hz), 7.78 (2H, d, J=8.7 Hz), 8.32
(2H, br), 8.92 (1H, br), 9.08 (1H, br s), 9.28 (1H, br s)
MS m/z: 521 (MH.sup.+) (5)
4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]ph
enyl]amino]carbonyl]-amino]-N,N-dimethylbenzamide
trifluroacetate
NMR (DMSO-d.sub.6, .delta.): 2.61-3.65 (7H, m), 2.96 (6H, s),
3.96-4.00 (2H, m), 4.20 (1H, br) 5.32 (1H, br), 5.89 (1H, br),
6.94-7.00 (3H, m), 7.20 (2H, d, J=8.5 Hz), 7.31 (2H, t, J=8.1 Hz),
7.35 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.7
Hz), 8.32 (1H, br), 8.67 (1H, br), 8.93 (1H, br s), 9.06 (1H, br
s)
MS m/z: 507 (MH.sup.+)
EXAMPLE 34
To a solution of
N-[4-[(2S)-2-amino-3-hydroxypropyl]phenyl]-N'-phenylurea
hydrochloride (222 mg) in ethanol (5.0 ml) were added successively
N,N-diisopropylethylamine (264 .mu.l) and
(2S)-2-[[4-(benzyloxy)phenoxy)methyl]oxirane (212 mg) and the
solution was refluxed for 13.5 hours. After cooling to room
temperature, the precipitates were collected by filtration, washed
with ethanol, and dried under reduced pressure to give
N-[4-[(2S)-2-[[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydr
oxypropyl]phenyl]-N'-phenylurea (166 mg) as a white solid.
MS m/z: 542 (MH.sup.+)
EXAMPLE 35
N-[4-[(2S)-2-[[(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydro
xypropyl]phenyl]-N'-phenylurea (159 mg) was dissolved in a mixed
solvent of methanol (2.5 ml) and 1,4-dioxane (2.5 ml) under
heating. After cooling to room temperature, 10% palladium on
activated carbon (50% wet, 159 mg) was added and the mixture was
hydrogenated at 1 atm for 4 hours. The catalyst was removed by
filtration and washed with methanol. The filtrate was concentrated
in vacuo to give
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]p
ropyl]phenyl]-N'-phenylurea (129 mg) as a white solid.
IR (KBr): 3456, 3296, 3033, 1643, 1595, 1560, 1511, 1442, 1230,
1101, 1041, 827 cm.sup.-1
NMR (DMSO-d.sub.6, .delta.): 2.55-2.78 (5H, m), 3.23 (2H, br),
3.73-3.82 (3H, m), 4.52 (1H, br), 4.89 (1H, br), 6.65 (2H, d, J=9.2
Hz), 6.74 (2H, d, J=9.2 Hz), 6.95 (1H, t-like, J=7.3 Hz), 7.09 (2H,
d, J=8.4 Hz), 7.25 (2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.4 Hz), 7.44
(2H, d, J=7.6 Hz), 8.57 (1H, br), 8.63 (1H, br), 8.87 (1H, br)
MS m/z: 452 (MH.sup.+)
EXAMPLE 36
To a solution of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino
)-1-propanol (300 mg) in 1,2-dichloroethane (3.0 ml) was added
N,O-bis(trimethylsilyl)acetamide (182 .mu.l) and the solution was
stirred at room temperature for 1 hour. To the solution were added
successively 4-(methoxycarbonyl)benzoic acid (160 mg),
1-hydroxybenzotriazole hydrate (120 mg), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (170
mg) at room temperature. After stirring at the same temperature for
3 hours, N,O-bis(trimethylsilyl)acetamide (182 .mu.l) was added and
the mixture was stirred overnight. The mixture was diluted with
ethyl acetate (30 ml) and washed with a saturated aqueous sodium
bicarbonate solution (30 ml.times.1), water (30 ml.times.2) and
brine (30 ml.times.1) successively, dried over magnesium sulfate,
and evaporated to give a yellow solid. The solid was dissolved in
tetrahydrofuran (3.0 ml). To the solution was added a 1.0 M
solution of tetrabutylammonium fluoride in tetrahydrofuran (1.48
ml) at room temperature and the solution was stirred for 10
minutes. The solution was diluted with ethyl acetate (20 ml) and
washed with water (20 ml.times.2) and brine (20 ml.times.1)
successively, dried over magnesium sulfate, and evaporated to give
a yellow solid. The crude product was purified by a recycling
preparative high pressure liquid chromatography equipped with a gel
permeation chromatography column (eluent: chloroform) and silica
gel chromatography (eluent: hexane/ethyl acetate=1/1) to give
methyl
4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydrox
ypropyl]phenyl]amino]carbonyl]benzoate (132 mg) as a pale yellow
solid.
MS m/z: 569 (MH.sup.+)
EXAMPLE 37
To a solution of methyl
4-[((4-[((2S)-2-(N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydro
xypropyl]-phenyl]amino]carbonyl]benzoate (30.0 mg) in methanol (1.0
ml) was added 10% palladium on activated carbon (50% wet, 30 mg)
and the mixture was hydrogenated at 1 atm for 2 hours. The catalyst
was filtered off and washed with methanol. The filtrate was
concentrated in vacuo to give methyl
4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]ph
enyl]amino]carbonyl]benzoate (21.9 mg) as a white solid.
EXAMPLE 38
To a suspension of methyl
4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phe
nyl]-amino]carbonyl]benzoate (19.3 mg) in methanol (1.0 ml) was
added 1N sodium hydroxide solution (40.3 .mu.l) and the suspension
was refluxed for 10 hours. An additional portion of 1N sodium
hydroxide solution (40.3 .mu.l) was added and the mixture was
refluxed for 3 hours. After cooling to room temperature, the
solvent was removed by evaporation to give sodium
4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phe
nyl]amino]carbonyl]benzoate (20.6 mg) as a white solid.
MS m/z: 487 (MH.sup.+)
EXAMPLE 39
To a solution of methyl
4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydrox
ypropyl]-phenyl]amino]carbonyl]benzoate (93.6 mg) in methanol (2.0
ml) was added 1N sodium hydroxide solution (329 .mu.l) and the
solution was refluxed for 2.5 hours. After cooling to room
temperature, the mixture was neutralized by the addition of 1N
hydrochloric acid (329 .mu.l). The solvent was removed by
evaporation and the residual solid was suspended in water (2.0 ml).
The solid was collected by filtration, washed with water, and dried
under reduced pressure to give
4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydrox
ypropyl]phenyl]amino]carbonyl]benzoic acid (80.2 mg) as a white
solid.
MS (negative) m/z: 553 (M-H.sup.+)
EXAMPLE 40
To a solution of
4-[[[4-((2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydrox
ypropyl]phenyl]-amino]carbonyl]benzoic acid (14.6 mg) in
N,N-dimethylformamide (200 .mu.l) were added 1.0 M solution of
1-hydroxybenzotriazole hydrate in N,N-dimethylformamide (31.6
.mu.l) and 1.0 M solution of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in
1,2-dichloroethane (31.6 .mu.l) at room temperature. To the mixture
was added methylamine hydrochloride (2.2 mg) and the whole was
stirred overnight. The reaction mixture was diluted with ethyl
acetate (10 ml) and washed with water (10 ml.times.1) and brine (10
ml.times.1) successively, dried over magnesium sulfate, and
evaporated to give a pale yellow paste. The crude product was
purified by a recycling preparative high pressure liquid
chromatography equipped with a gel permeation chromatography column
(eluent: chloroform) to give N.sup.1
-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypr
opyl]-phenyl]-N.sup.4 -methylterephthalamide (14.0 mg) as a white
solid.
EXAMPLE 41
The following compounds were obtained according to a similar manner
to that of Example 40. (1) N.sup.1
-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypr
opyl]phenyl]-N.sup.4,N.sup.4 -dimethylterephthalamide (2) N.sup.1
-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypr
opyl]phenyl]-N.sup.4 -propylterephthalamide
EXAMPLE 42
To a solution of N.sup.1
-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypr
opyl]phenyl]-N.sup.4 -methylterephthalamide (14.0 mg) in methanol
(0.5 ml) was added 10% palladium on activated carbon (50% wet, 14.0
mg) and the mixture was hydrogenated at 1 atm for 3 hours. The
catalyst was filtered off and washed with methanol. The filtrate
was concentrated in vacuo to give N.sup.1
-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]-pheny
l]-N.sup.4 -methylterephthalamide (9.7 mg) as a white solid.
MS m/z: 478 (MH.sup.+)
EXAMPLE 43
The following compounds were obtained according to a similar manner
to that of Example 42. (1) N.sup.1
-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl
]-N.sup.4,N.sup.4 -dimethylterephthalamide
MS m/z: 492 (MH.sup.+) (2) N.sup.1
-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl
]-N.sup.4 -propylterephthalamide
MS m/z: 505 (MH.sup.+)
EXAMPLE 44
To a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropy
l]carbamate (200 mg) in N,N-dimethylformamide (2.0 ml) was added
successively 1-methyl-1H-pyrrole-2-caroxylic acid (72.1 mg) and
1-hydroxybenzotriazole hydrate (77.9 mg). To the mixture was added
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (110
mg) at room temperature and the mixture was stirred overnight. The
mixture was diluted with ethyl acetate (20 ml) and washed with
water (20 ml.times.2), a saturated aqueous sodium hydrogencarbonate
solution (20 ml.times.1) and brine (20 ml.times.1) successively.
The organic solution was dried over magnesium sulfate, filtered,
and evaporated to give a yellow solid. The crude product was
purified by a recycling preparative high pressure liquid
chromatography equipped with a gel permeation chromatography column
(eluent: chloroform) to give tert-butyl
N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]et
hyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (163 mg) as a
white foam.
MS (ESI) m/z: 546 (M+Na.sup.+)
EXAMPLE 45
The following compounds were obtained according to a similar manner
to that of Example 44. (1) tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[(2-phenoxy-3-p
yridyl)carbonyl]amino]-benzyl]ethyl]carbamate
MS m/z: 636 (M+Na.sup.+) (2) tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(8-quinolinylca
rbonyl)amino]benzyl]-ethyl]carbamate
MS m/z: 594 (M+Na.sup.+) (3) tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[[5-[4-(trifluo
romethyl)phenyl]-1,3-oxazol-4-yl]carbonyl]amino]benzyl]ethyl]carbamate
MS m/z: 678 (M+Na.sup.+) (4) tert-Butyl
N-[(1S)-2-hydroxy-1-[4-[[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]amino
]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate
MS m/z: 623 (M+Na.sup.+) (5) tert-Butyl
N-[(1S)-2-hydroxy-1-[4-[[(2-methyl-1H-benzimidazol-5-yl)carbonyl]amino]ben
zyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl)carbamate
MS m/z: 597 (M+Na.sup.+) (6) tert-Butyl
N-[(1S)-2-hydroxy-1-[4-[(1H-indol-5-ylcarbonyl)amino]benzyl]ethyl]-N-[(2S)
-2-hydroxy-3-phenoxypropyl]carbamate
MS m/z: 582 (M+Na.sup.+) (7) tert-Butyl
N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-indol-3-yl)carbonyl]amino]benzyl]eth
yl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate
MS m/z: 596 (M+Na.sup.+) (8) tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-3-yl
carbonyl)amino]-benzyl]ethyl]carbamate
MS m/z: 532 (M+Na.sup.+) (9) tert-Butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-2-yl
carbonyl)amino]benzyl]-ethyl]carbamate
NMR (CDCl.sub.3, .delta.): 1.46 (9H, s), 2.35-4.45 (10H, m),
6.21-6.36 (1H, m), 6.60-7.35 (9H, m), 7.51 (2H, d, J=8 Hz), 7.58
(1H, br s), 9.59 (1H, br s)
MS m/z: 532 (M.sup.+ +Na)
EXAMPLE 46
tert-Butyl
N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]et
hyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (158 mg) was
dissolved in 4N hydrogen chloride in ethanol (2.0 ml) and the
solution was stirred at room temperature for 2 hours. The solvent
was removed by evaporation and the residual solid was dried under
reduced pressure to give
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (125 mg) as a
pale orange crystalline solid.
MS m/z: 424 (M+Na.sup.+)
EXAMPLE 47
The following compounds were obtained according to a similar manner
to that of Example 46. (1)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-2-phenoxynicotinamide hydrochloride
MS m/z: 514 (MH.sup.+) (2)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-8-quinolinecarboxamide dihydrochloride
MS m/z: 472 (MH.sup.+) (3)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-5-[4-(trifluoromethyl)phenyl]-1,3-oxazole-4-carboxamide
hydrochloride
MS m/z: 556 (M+Na.sup.+) (4)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide hydrochloride
MS m/z: 501 (M+Na.sup.+) (5)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-2-methyl-1H-benzimidazole-5-carboxamide dihydrochloride
MS m/z: 475 (MH.sup.+) (6)
N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]pheny
l]-1H-indole-5-carboxamide hydrochloride
MS m/z: 460 (M+Na.sup.+) (7)
N-[(4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phen
yl]-1-methyl-1H-indole-3-carboxamide hydrochloride
MS m/z: 474 (MH.sup.+)
EXAMPLE 48
To a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydoxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydr
oxyethyl]carbamate (120 mg) in N,N-dimethylformamide (2.0 ml) was
added successively 4-phenyl-1H-pyrrole-3-carboxylic acid (64.0 mg)
and 1-hydroxybenzotriazole hydrate (46.2 mg). To the mixture was
added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(65.6 mg) at room temperature and the mixture was stirred
overnight. The mixture was diluted with ethyl acetate (20 ml) and
washed with water (20 ml.times.2), a saturated aqueous sodium
hydrogencarbonate solution (20 ml.times.1) and brine (20
ml.times.1) successively. The organic solution was dried over
magnesium sulfate, filtered, and evaporated to give a yellow solid.
The crude product was purified by a recycling preparative high
pressure liquid chromatography equipped with a gel permeation
chromatography column (eluent: chloroform) to give tert-butyl
N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(4-phe
nyl-1H-pyrrol-3-yl)carbonyl]amino]benzyl]ethyl]carbamate (16 mg) as
a yellow foam.
MS (ESI) m/z: 612 (M+Na.sup.+)
EXAMPLE 49
The following compounds were obtained according to a similar manner
to that of Example 48. (1) tert-Butyl
N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(1-met
hyl-1H-indol-5-yl)carbonyl]amino]benzyl]ethyl]carbamate
MS (ESI) m/z: 600 (M+Na.sup.+) (2) Methyl
4-[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydro
xyethyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]benzoate
MS m/z: 483 and 485 (MH.sup.+ -100)
EXAMPLE 50
tert-Butyl
N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(4-phe
nyl-1H-pyrrol-3-yl)carbonyl]amino]benzyl]ethyl]carbamate (13.3 mg)
was dissolved in 4N hydrogen chloride in ethanol (0.5 ml) and the
solution was stirred at room temperature for 5 hours. The solvent
was removed by evaporation to give
N-[4-(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropy
l]phenyl]-4-phenyl-1H-pyrrole-3-carboxyamide hydrochloride (12.8
mg) as a pale yellow solid.
MS m/z: 490 (MH.sup.+)
EXAMPLE 51
The following compounds were obtained according to a similar manner
to that of Example 50. (1) Methyl
4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypr
opyl]phenyl]amino]-carbonyl]benzoate hydrochloride
MS m/z: 483 (MH.sup.+) (2)
N-[4-[(2S)-3-Hydroxy-2-[[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phen
yl]-1H-pyrrole-2-carboxamide hydrochloride
NMR (DMSO-d.sub.6, .delta.) 2.70-3.75 (7H, m), 3.84-4.12 (2H, m),
4.12-4.40 (1H, m), 5.41 (1H, m), 5.89 (1H, m), 6.16 (1H, m),
6.80-7.12 (5H, m), 7.12-7.44 (4H, m), 7.72 (2H, d, J=8 Hz), 8.42
(1H, br s), 8.93 (1H, br s), 9.81 (1H, br s), 11.70 (1H, br s)
MS m/z: 410 (M.sup.+ +1)
EXAMPLE 52
tert-Butyl
N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-(4-[[(1-met
hyl-1H-indol-5-yl)carbonyl]amino]benzyl]ethyl]carbamate (101 mg)
was dissolved in 4N hydrogen chloride in ethanol (1.0 ml) and the
solution was stirred at room temperature for 5 hours. The solvent
was removed by evaporation and the residual solid was dissolved in
methanol. To the solution was added 1N sodium hydroxide solution
(175 .mu.l) and the solvent was removed by evaporation. The residue
was chromatographed on silica gel (eluent: chloroform/methanol=9/1)
to give
N-[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxyprop
yl]phenyl]-1-methyl-1H-indole-5-carboxamide (34.2 mg) as a pale
yellow solid.
MS m/z: 478 (MH.sup.+)
EXAMPLE 53
To a suspension of methyl
4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypr
opyl]-phenyl]amino]carbonyl]benzoate hydrochloride (101 mg) in
methanol (4.0 ml) was added 1N sodium hydroxide solution (486
.mu.l) and the mixture was refluxed for 90 minutes. After cooling
to room temperature, the solvent was removed by evaporation. The
residual solid was applied on a solid phase extraction cartridge
(BOND ELUT C18, 20 ml, VARIAN) and eluted with water and methanol
successively. The eluents containing the target compound were
combined and concentrated in vacuo to give sodium
4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypr
opyl]-phenyl]amino]carbonyl]benzoate (66.7 mg) as an off-white
solid.
MS m/z: 491 (MH.sup.+)
EXAMPLE 54
To a stirred suspension of
(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydr
oxypropyl]amino]-1-propanol (51.3 mg), 1H-pyrrole-2-carboxylic acid
(11.9 mg) and 1-hydroxybenzotriazole hydrate (13.5 mg) in
1,2-dichloromethane (1.0 ml) was added
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.5
mg) under ice-cooling and the resulting mixture was stirred at room
temperature overnight. The mixture was diluted with saturated
aqueous sodium hydrogencarbonate solution and extracted twice with
ethyl acetate. The extracts were combined, washed twice with brine,
dried over magnesium sulfate, and concentrated in vacuo. The
residue was purified by preparative thin layer chromatography
(eluent: toluen/ethyl acetate=5/5) to give
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]-a
mino]-3-hydroxypropyl]phenyl]-1H-pyrrole-2-carboxamide (43 mg) as a
gum.
MS m/z: 606 (MH.sup.+)
EXAMPLE 55
To a solution of
N-[4-[(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]am
ino]-3-hydroxypropyl]-phenyl]-1H-pyrrole-2-carboxamide (40 mg) in
methanol (2.0 ml) was added 10% palladium on activated carbon (50%
wet, 10 mg) and the mixture was hydrogenated at 1 atm for 3 hours.
The catalyst was filtered off and washed with methanol. The
filtrate was concentrated in vacuo and the residue was powdered
from ether and dried to give
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]p
ropyl]-phenyl]-1H-pyrrole-2-carboxamide (26 mg) as a gray
powder.
MS m/z: 426 (MH.sup.+)
EXAMPLE 56
Under nitrogen, a solution of
(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]benzamide (60 mg) and
(S)-4-(2-oxiranylmethoxy)carbazole (42.5 mg) in ethanol (10 ml) was
refluxed for 18 hours. The mixture was evaporated in vacuo. The
residue was purified by column chromatography on silica gel
(chloroform:methanol=100:1) to give
N-[4-[((2S)-2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-3-hydr
oxypropyl]phenyl]benzamide (50 mg) as a colorless foam.
IR (KBr): 3300-3000, 1725, 1650, 1602, 1511, 1446, 1259
cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.50-3.10 (4H, m), 3.20-3.70 (3H, m),
4.10-4.00 (3H, m), 6.60 (1H, d, J=7.8 Hz), 7.05-8.00 (14H, m), 8.3
(1H, d, J=7.8 Hz)
MS m/z: 510 (M+1)
EXAMPLE 57
The following compounds were obtained according to a similar manner
to that of Example 56. (1)
N-[4-[(2S)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxyprop
yl]phenyl]benzamide
IR (KBr): 3500-3000, 1650, 1598, 1515, 1411, 1321, 1263
cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.70-3.20 (4H, m), 3.40-3.80 (3H, m),
4.70-4.80 (1H, m), 7.10-7.70 (11H, m), 7.90-8.00 (2H, m)
MS m/z: 425 (M+1) (2)
N-[4-[(2S)-2-[[(2S)-3-(1H-Indoly-4-yloxy)-2-hydroxypropyl]amino]1-3-hydrox
ypropyl]phenyl]benzamide
IR (KBr): 3400-3000, 1658, 1646, 1598, 1513, 1444, 1241, 1091
cm.sup.-1
NMR (MeOD-d.sub.4, .delta.): 2.70-3.20 (5H, m), 3.30-3.70 (2H, m),
4.00-4.25 (3H, m), 6.40-6.60 (2H, m), 6.90-8.00 (12H, m)
MS m/z: 460 (M+1)
EXAMPLE 58
In 4N hydrogen chloride in ethanol (2.0 ml), tert-butyl
N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-3-yl
carbonyl)amino]benzyl]ethyl]carbamate (113.5 mg) was dissolved and
the solution was stirred at room temperature for 30 hours. After
concentration under reduced pressure, the residue was extracted
with ethyl acetate (20 ml) and washed with saturated sodium
hydrogencarbonate aqueous solution (20 ml). The organic layer was
separated and the aqueous layer was extracted twice with ethyl
acetate (20 ml). The organic layers were combined and washed with
brine, and dried over magnesium sulfate to give
N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]-phen
yl]-1H-pyrrole-3-carboxamide (18.2 mg) as a yellow solid.
MS m/z: 410 (MH.sup.+), 432 (M+Na.sup.+)
EXAMPLE 59
Step 1: Preparation of Polymer-Bound HOBt ester (1) ##STR15##
Polystyrene-bound 1-hydroxybenzotriazole (HOBt),
bis-(6-carboxy-HOBt)-N-(2-aminoethyl)aminomethyl polystyrene (200
mg, 1.54 mmole/g, Novabiochem) was added to a 6 ml polypropylene
tube (Varian). A solution of a carboxylic acid derivative
##STR16##
or hydrochloride thereof corresponding to an objective amide
derivative in N,N-dimethylformamide (DMF) (0.4 M, 2.3 ml) was added
to the tube and shaken for 5 minutes. To the reaction mixture was
added 1,3-diisopropylcarbodiimide (72.4 .mu.l) and shaken for 3
hours at ambient temperature. The resin was filtered and washed
well with DMF. An additional 2.3 ml of 0.4 M carboxylic acid
derivative solution in DMF and 1,3-diisopropylcarbodiimide (72.4
.mu.l) were added and shaken for 3 hours at ambient temperature.
The resultant resin was filtered, washed well subsequently with
DMF, dichloromethane (DCM), diethyl ether, and dried under reduced
pressure to give polymer-bound HOBt ester (1).
Step 2: General Procedure for the Amide Derivatives (2)
##STR17##
To a 6 ml polypropylene tube (Varian) was added 0.024 M solution of
tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropy
l]carbamate in DCM (1 ml) and N,O-bis(trimethylsilyl)acetamide (18
.mu.l). After shaking for 30 minutes, polymer-bound HOBt ester (100
mg) was added to the reaction mixture and shaken overnight at
ambient temperature. The polymer was filtered, washed well with DCM
and concentrated under reduced pressure. To the resultant residue
was added 1 ml of 50% trifluoroacetic acid (TFA) in DCM and shaken
for 3 hours at ambient temperature. The solvent was evaporated and
purified by HPLC (reverse phase C.sub.18, 0-80% 0.1% TFA in
acetonitrile/0.1% TFA in water. The fractions containing the
desired compound were combined, evaporated and dried under reduced
pressure to give the objective amide derivative (2).
Following the Steps 1 and 2 outlined above, the compounds listed in
Table 1 were obtained.
TABLE 1 ##STR18## .cndot.pCF.sub.3 CO.sub.2 H (p = 1 or 2) Example
B p MS [M + H].sup.+ Data 59-(1) ##STR19## 1 455 59-(2) ##STR20## 1
411 59-(3) ##STR21## 1 437 59-(4) ##STR22## 1 481 59-(5) ##STR23##
1 411 59-(6) ##STR24## 1 427 59-(7) ##STR25## 1 427 59-(8)
##STR26## 1 460 59-(9) ##STR27## 1 477 59-(10) ##STR28## 2 450
59-(11) ##STR29## 2 473 59-(12) ##STR30## 1 451 59-(13) ##STR31## 1
475
EXAMPLE 60
General Procedure for the Amide Derivatives (3) ##STR32##
To a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-[(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-
2-[(trimethylsilyl)oxy]propyl]carbamate in N,N-dimethylformamide
(DMF) (0.059 M, 300 .mu.l) was added a carboxylic acid derivative
##STR33##
or hydrochloride thereof corresponding to an objective amide
derivative (21.4 .mu.M) and a solution of
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
in DMF (0.142 M, 150 .mu.l). After shaking for 5 minutes, to the
reaction mixture was added N,N-diisopropylethylamine (DIEA, 7.8
.mu.l) and shaken overnight at ambient temperature. In the case
that 3-pyridylacetic acid was used as a carboxylic acid derivative,
additional 15.6 .mu.l of DIEA was added to the reaction mixture.
The reaction mixture was loaded onto the solid-phase extraction
cartridge (Waters, Oasis) conditioned using acetonitrile (CH.sub.3
CN, 6 ml) and water (6 ml), washed with water (6 ml) and 10%
CH.sub.3 CN in water (6 ml), and eluted with CH.sub.3 CN (6 ml).
Evaporation of the solvent gave a residue, to which was added 50%
trifluoroacetic acid in dichloromethane (DCM) (1 ml) and shaken for
3 hours at ambient temperature. Evaporation of the solvent gave a
residue, which was purified by HPLC (reverse phase C.sub.18, 0-80%
0.1% TFA in CH.sub.3 CN/0.1% TFA in water). The fractions
containing the desired compound were combined, evaporated and dried
under reduced pressure to give the objective amide derivative
(3).
Following the procedure outlined above, the compounds listed in
Table 2 were obtained.
TABLE 2 ##STR34## .cndot.pCF.sub.3 CO.sub.2 H (p = 1 or 2) Example
B p MS [M + H].sup.+ Data 60-(1) ##STR35## 1 422 60-(2) ##STR36## 1
474 60-(3) ##STR37## 1 427 60-(4) ##STR38## 1 457 60-(5) ##STR39##
2 436 60-(6) ##STR40## 2 422 60-(7) ##STR41## 1 472 60-(8)
##STR42## 1 472 60-(9) ##STR43## 2 411 60-(10) ##STR44## 1 460
60-(11) ##STR45## 1 461 60-(12) ##STR46## 1 486 60-(13) ##STR47## 1
475 60-(14) ##STR48## 1 474 60-(15) ##STR49## 1 435 60-(16)
##STR50## 1 435 60-(17) ##STR51## 1 435 60-(18) ##STR52## 1 439
60-(19) ##STR53## 1 439 60-(20) ##STR54## 1 439 60-(21) ##STR55## 1
466 60-(22) ##STR56## 1 466 60-(23) ##STR57## 1 466 60-(24)
##STR58## 1 489 60-(25) ##STR59## 1 489 60-(26) ##STR60## 1 489
EXAMPLE 61
General Procedure for the Amide Derivatives (4) ##STR61##
Method A
To a solution of a carboxylic acid derivative ##STR62##
corresponding to an objective amide derivative (0.024 mmol) in NMP
(36 .mu.l) was added 1.0 M solution of
N,O-bis(trimethylsilyl)acetamide (BSA) in N-methyl-2-pyrrolidinone
(NMP) (12 .mu.l, 0.012 mmol). After shaking for 30 minutes at room
temperature, 1.0 M solution of N,N-diisopropylethylamine (DIEA) in
NMP (50 .mu.l, 0.05 mmol) and 0.5 M solution of
benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate
in NMP (60 .mu.l, 0.03 mmol) were added to the solution and the
mixture was shaken for 30 minutes at room temperature. In another
vessel, a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hyd
roxyethyl]carbamate (0.02 mmol) in NMP (20 .mu.l) and 1.0 M
solution of BSA in NMP (20 .mu.l, 0.02 mmol) was shaken for 30
minutes at room temperature, and the solution was added to the
above activated ester solution. The mixture was allowed to warm to
50.degree. C. and shaken for 2 hours. After cooling to room
temperature, 0.5 ml of 95% trifluoroacetic acid (TFA) in water was
added to the solution and shaken for 15 hours. The mixture was
concentrated under reduced pressure and purified by HPLC (reverse
phase C.sub.18, 0-80% 0.1% TFA in acetonitrile (CH.sub.3 CN)/0.1%
TFA in water. The fractions containing the desired compound were
combined, concentrated and dried under reduced pressure to give the
objective amide derivative (4).
Method B
To a solution of a carboxylic acid derivative ##STR63##
or hydrochloride thereof corresponding to an objective amide
derivative (0.024 mmol) in NMP (36 .mu.l) was added 1.0 M solution
of BSA in NMP (12 l, 0.012 mmol). After shaking for 30 minutes at
room temperature, 0.5 M solution of 1-hydroxybenzotriazole (HOBt)
in NMP (60 .mu.l, 0.03 mmol) and 0.5 M solution of 1-ethyl
3-(3'-dimethylaminopropyl)carbodiimide (EDC) in NMP (60 .mu.l, 0.03
mmol) were added to the solution and the mixture was shaken for 30
minutes at room temperature. In another vessel, a solution of
tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hyd
roxyethyl]carbamate (0.02 mmol) in NMP (20 .mu.l) and 1.0 M
solution of BSA in NMP (20 .mu.l, 0.02 mmol) was shaken for 30
minutes at room temperature, and the solution was added to the
above activated ester solution. The mixture was allowed to warm to
50.degree. C. and shaken for 15 hours. After cooling to room
temperature, 0.5 ml of 95% TFA in water was added to the solution
and shaken for 15 hours. The mixture was concentrated under reduced
pressure and purified by HPLC (reverse phase C.sub.18, 0-80% 0.1%,
TFA in CH.sub.3 CN/0.1% TFA in water). The fractions containing the
desired compound were combined, concentrated and dried under
reduced pressure to give the objective amide derivative (4).
Following Method A or Method B outlined above, the compounds listed
in Table 3 were obtained.
TABLE 3 ##STR64## .cndot.CF.sub.3 CO.sub.2 H Example B MS [M +
H].sup.+ Data Method 61-(1) ##STR65## 426, 428 A 61-(2) ##STR66##
427, 429 A 61-(3) ##STR67## 431, 433 A 61-(4) ##STR68## 415, 416 A
61-(5) ##STR69## 475 A 61-(6) ##STR70## 476, 477 A 61-(7) ##STR71##
476, 477 A 61-(8) ##STR72## 476 A 61-(9) ##STR73## 476, 477 A
61-(10) ##STR74## 477, 478 A 61-(11) ##STR75## 585, 586 A 61-(12)
##STR76## 428 A 61-(13) ##STR77## 518 A 61-(14) ##STR78## 455 A
61-(15) ##STR79## 455 A 61-(16) ##STR80## 455, 456 A 61-(17)
##STR81## 426 A 61-(18) ##STR82## 426 A 61-(19) ##STR83## 431 A
61-(20) ##STR84## 415 A 61-(21) ##STR85## 522, 523 A 61-(22)
##STR86## 476, 478 A 61-(23) ##STR87## 476 A 61-(24) ##STR88## 475,
476 A 61-(25) ##STR89## 476, 477 A 61-(26) ##STR90## 478 A 61-(27)
##STR91## 506 A 61-(28) ##STR92## 495 A 61-(29) ##STR93## 459, 461
A 61-(30) ##STR94## 459, 461 A 61-(31) ##STR95## 459 A 61-(32)
##STR96## 478, 479 A 61-(33) ##STR97## 414 B 61-(34) ##STR98## 464
B 61-(35) ##STR99## 464, 465 B 61-(36) ##STR100## 478 B 61-(37)
##STR101## 478 B 61-(38) ##STR102## 481, 482 B 61-(39) ##STR103##
466 B 61-(40) ##STR104## 482, 484 B 61-(41) ##STR105## 506, 507 A
61-(42) ##STR106## 477 A 61-(43) ##STR107## 414 B 61-(44)
##STR108## 490, 491 B
EXAMPLE 62
General Procedure for the Amide Derivatives (5) ##STR109##
A mixture of a carboxylic acid derivative ##STR110##
corresponding to an objective amide derivative (0.024 mmol) and 1.0
M pyridine in 1,2-dichloroethane (DCE) (24 .mu.l) was treated with
1.0 M solution of oxallyl chloride in DCE (26 .mu.l) at room
temperature. After stirring for 1 hour, the mixture was diluted
with N-methyl-2-pyrrolidinone (NMP) (20 .mu.l). To a solution of
tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-hydroxy-3-phenoxypropy
l]carbamate (0.02 mmol) in NMP (20 .mu.l) was added 1.0 M solution
of N,O-bis(trimethylsilyl)acetamide (BSA) in NMP (20 .mu.l, 0.02
mmol), and the solution was stirred at room temperature. After
stirring for 30 minutes, the solution was added to the acid
chloride solution. After further stirring at 50.degree. C. for 30
minutes, the reaction mixture was treated with 95% trifluoroacetic
acid (TFA) in water (500 .mu.l) at 50.degree. C. for 30 minutes.
The mixture was concentrated under reduced pressure and the residue
was purified by HPLC (reverse phase C.sub.18, 0-80% 0.1% TFA in
acetonitrile/0.1% TFA in water). The fractions containing the
desired compound were combined, concentrated and dried under
reduced pressure to give the objective amide derivative (5).
Following the procedure outlined above, the compounds listed in
Table 4 were obtained.
TABLE 4 ##STR111## .cndot.CF.sub.3 CO.sub.2 H Example B MS [M +
H].sup.+ Data 62-(1) ##STR112## 565 62-(2) ##STR113## 460 62-(3)
##STR114## 440 62-(4) ##STR115## 526 62-(5) ##STR116## 497 62-(6)
##STR117## 456 62-(7) ##STR118## 512 62-(8) ##STR119## 488 62-(9)
##STR120## 498 62-(10) ##STR121## 487 62-(11) ##STR122## 514
62-(12) ##STR123## 488 62-(13) ##STR124## 486 62-(14) ##STR125##
487 62-(15) ##STR126## 497 62-(16) ##STR127## 497
EXAMPLE 63
General Procedure for the Amide Derivatives (6) ##STR128##
The amide derivatives above were obtained according to a similar
manner to that of Example 62 using tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hyd
roxyethyl]carbamate instead of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-hydroxy-3-phenoxypropy
l]carbamate.
Following the procedure outlined above, the compounds listed in
Table 5 were obtained.
TABLE 5 ##STR129## .cndot.CF.sub.3 CO.sub.2 H Example B MS [M +
H].sup.+ Data 63-(1) ##STR130## 570 63-(2) ##STR131## 464 63-(3)
##STR132## 506 63-(4) ##STR133## 444 63-(5) ##STR134## 531 63-(6)
##STR135## 502 63-(7) ##STR136## 460 63-(8) ##STR137## 516 63-(9)
##STR138## 493 63-(10) ##STR139## 503 63-(11) ##STR140## 491
63-(12) ##STR141## 518 63-(13) ##STR142## 490 63-(14) ##STR143##
492 63-(15) ##STR144## 502 63-(16) ##STR145## 502 63-(17)
##STR146## 560
EXAMPLE 64
General Procedure for the Urea Derivatives (7) ##STR147##
To a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-hydroxy-3-phenoxypropy
l]carbamate (0.02 mmol) in N-methyl-2-pyrrolidinone (NMP) (40
.mu.l) was added 2.0 M solution of N,O-bis(trimethylsilyl)acetamide
(BSA) in NMP (10 pl, 0.02 mmol) at room temperature. After stirring
for 30 minutes, 1.0 M solution of an isocyanate derivative
(O.dbd.C=N--B) corresponding to an objective urea derivative in NMP
(24 pl, 0.024 mmol) and 0.1 M solution of N,N-diisopropylethylamine
(DIEA) in NMP (20 .mu.l, 0.002 mmol) were added to the solution.
After further stirring at 50.degree. C. for 30 minutes, the
reaction mixture was treated with 95% trifluoroacetic acid (TFA) in
water (500 .mu.l) at 50.degree. C. for 30 minutes. The mixture was
concentrated under reduced pressure and the residue was purified by
HPLC (reverse phase C.sub.18, 0-80% 0.1% TFA in acetonitrile/0.1%
TFA in water). The fractions containing the desired compound were
combined, concentrated and dried under reduced pressure to give the
objective urea derivative (7).
Following the procedure outlined above, the compounds listed in
Table 6 were obtained.
TABLE 6 ##STR148## .cndot.CF.sub.3 CO.sub.2 H Example B MS [M +
H].sup.+ Data 64-(1) ##STR149## 450 64-(2) ##STR150## 470 64-(3)
##STR151## 515 64-(4) ##STR152## 466 64-(5) ##STR153## 504 64-(6)
##STR154## 512 64-(7) ##STR155## 512 64-(8) ##STR156## 528 64-(9)
##STR157## 528 64-(10) ##STR158## 528 64-(11) ##STR159## 520
64-(12) ##STR160## 520 64-(13) ##STR161## 486 64-(14) ##STR162##
486 64-(15) ##STR163## 505 64-(16) ##STR164## 505 64-(17)
##STR165## 505
EXAMPLE 65
General Procedure for the Amide Derivatives (8) ##STR166##
The amide derivatives above were obtained according to a similar
manner to that of Example 64 using an acyl chloride derivative
##STR167##
instead of an isocyanate derivative (O.dbd.C.dbd.N--B).
Following the procedure above, the compounds listed in Table 7 were
obtained.
TABLE 7 ##STR168## .cndot.CF.sub.3 CO.sub.2 H Example X.sub.3 --B
MS [M + H].sup.+ Data 65-(1) ##STR169## 450 65-(2) ##STR170##
428
EXAMPLE 66
General Procedure for the Urea Derivatives (9) ##STR171##
To a solution of tert-butyl
N-[(1s)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hyd
roxyethyl]-carbamate (0.02 mmol) in NMP (40 ul) was added 2.0 M
solution of N,O-bis(trimethylsilyl)acetamide (BSA) in
N-methyl-2-pyrrolidinone (NMP) (10 .mu.l, 0.02 mmol) and the
mixture was shaken for 30 minutes at room temperature. To the
solution, 1.0 M solution of an isocyanate derivative
(O.dbd.C.dbd.N--B) corresponding to an objective urea derivative in
NMP (24 .mu.l, 0.024 mmol) and 0.1 M solution of
N,N-diisopropylethylamine (DIEA) in NMP (20 .mu.l, 0.002 mmol) were
added and the mixture was shaken for 30 minutes at 50.degree. C.
After cooling to room temperature, 0.5 ml of 95% trifluoroacetic
acid (TFA) in water was added to the solution and shaken for 15
hours. The mixture was concentrated under reduced pressure and
purified by HPLC (reverse phase C.sub.18, 0-80% 0.1% TFA in
acetonitrile/0.1% TFA in water). The fractions containing the
desired compound were combined, concentrated and dried under
reduced pressure to give the objective urea derivative (9).
Following the procedure outlined above, the compounds listed in
Table 8 were obtained.
TABLE 8 ##STR172## .cndot.CF.sub.3 CO.sub.2 H Example B MS [M +
H].sup.+ Data 66-(1) ##STR173## 474 66-(2) ##STR174## 474 66-(3)
##STR175## 474 66-(4) ##STR176## 470 66-(5) ##STR177## 470 66-(6)
##STR178## 470 66-(7) ##STR179## 406, 408 66-(8) ##STR180## 406
66-(9) ##STR181## 454, 456
EXAMPLE 67
General Procedure for the Amide Derivatives (10) ##STR182##
The amide derivatives above were obtained according to a similar
manner to that of Example 66 using an acyl chloride derivative
##STR183##
corresponding to an objective amide derivative instead of an
isocyanate derivative (O.dbd.C.dbd.N--B).
Following the procedure above, the compounds listed in Table 9 were
obtained.
TABLE 9 ##STR184## .cndot.CF.sub.3 CO.sub.2 H Example X.sub.3 --B
MS [M + H].sup.+ Data 67-(1) ##STR185## 454 67-(2) ##STR186##
432
EXAMPLE 68
General Procedure for the Urea Derivatives (11) ##STR187##
To a 0.5 M solution of an amine derivative (.sup.H.sub.H.sup.N-B)
corresponding to an objective urea derivative in
N-methyl-2-pyrrolidinone (NMP) (50.mu., 0.025 mmol) was added 1.0 M
solution of 1,1'-carbonyldiimidazole (CDI) (26.3 .mu.l, 0.0263
mmol) and the mixture was shaken for 30 minutes at room
temperature. In another vessel, a solution of tert-butyl
N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl-3-N-[(2R)-2-(3-chlorophenyl)-2-hy
droxyethyl]carbamate (0.02 mmol) in NMP (20 .mu.l) and 1.0 M
solution of N,O-bis(trimethylsilyl)-acetamide (BSA) in NMP (20
.mu.l, 0.02 mmol) was shaken for 30 minutes at room temperature,
and the solution was added to the above solution. After shaking for
2 hours, 0.5 ml of 95% trifluoroacetic acid (TFA) in water was
added to the solution and shaken for 15 hours. The mixture was
concentrated under reduced pressure and purified by HPLC (reverse
phase C.sub.18, 0-80% 0.1% TFA in acetonitrile/0.1% TFA in water).
The fractions containing the desired compound were combined,
concentrated and dried under reduced pressure to give the objective
urea derivative (11).
Following the procedure outlined above, the compounds listed in
Table 10 were obtained.
TABLE 10 ##STR188## Example B MS [M + H].sup.+ Data 68-(1)
##STR189## 446 68-(2) ##STR190## 441, 442 68-(3) ##STR191## 491,
492 68-(4) ##STR192## 491 68-(5) ##STR193## 491, 493 68-(6)
##STR194## 491, 493 68-(7) ##STR195## 491, 492
* * * * *